Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

ABSTRACT

Compounds of Formula (I) 
                 
 
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, Y, and n are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

RELATED APPLICATIONS

This application claims benefit of U.S. Ser. No. 60/404,901, filed Aug.21, 2002, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to glucocorticoid mimetics or ligands,methods of making such compounds, their use in pharmaceuticalcompositions, and their use in modulating the glucocorticoid receptorfunction, treating disease-states or conditions mediated by theglucocorticoid receptor function in a patient in need of such treatment,and other uses.

BACKGROUND OF THE INVENTION

Glucocorticoids, a class of corticosteroids, are endogenous hormoneswith profound effects on the immune system and multiple organ systems.They suppress a variety of immune and inflammatory functions byinhibition of inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF,inhibition of arachidonic acid metabolites including prostaglandins andleukotrienes, depletion of T-lymphocytes, and reduction of theexpression of adhesion molecules on endothelial cells (P. J. Barnes,Clin. Sci., 1998, 94, pp. 557-572; P. J. Barnes et al., TrendsPharmacol. Sci., 1993, 14, pp. 436-441). In addition to these effects,glucocorticoids stimulate glucose production in the liver and catabolismof proteins, play a role in electrolyte and water balance, reducecalcium absorption, and inhibit osteoblast function.

The anti-inflammatory and immune suppressive activities of endogenousglucocorticoids have stimulated the development of syntheticglucocorticoid derivatives including dexamethasone, prednisone, andprednisolone (L. Parente, Glucocorticoids, N. J. Goulding and R. J.Flowers (eds.), Boston: Birkhauser, 2001, pp. 35-54). These have foundwide use in the treatment of inflammatory, immune, and allergicdisorders including rheumatic diseases such as rheumatoid arthritis,juvenile arthritis, and ankylosing spondylitis, dermatological diseasesincluding psoriasis and pemphigus, allergic disorders including allergicrhinitis, atopic dermatitis, and contact dermatitis, pulmonaryconditions including asthma and chronic obstructive pulmonary disease(COPD), and other immune and inflammatory diseases including Crohndisease, ulcerative colitis, systemic lupus erythematosus, autoimmunechronic active hepatitis, osteoarthritis, tendonitis, and bursitis (J.Toogood, Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.),Boston: Birkhauser, 2001, pp. 161-174). They have also been used to helpprevent rejection in organ transplantation.

Unfortunately, in addition to the desired therapeutic effects ofglucocorticoids, their use is associated with a number of adverse sideeffects, some of which can be severe and life-threatening. These includealterations in fluid and electrolyte balance, edema, weight gain,hypertension, muscle weakness, development or aggravation of diabetesmellitus, and osteoporosis. Therefore, a compound that exhibited areduced side effect profile while maintaining the potentanti-inflammatory effects would be particularly desirable especiallywhen treating a chronic disease.

The effects of glucocorticoids are mediated at the cellular level by theglucocorticoid receptor (R. H. Oakley and J. Cidlowski, Glucocorticoids,N. J. Goulding and R. J. Flowers (eds.), Boston: Birkhauser, 2001, pp.55-80). The glucocorticoid receptor is a member of a class ofstructurally related intracellular receptors that when coupled with aligand can function as a transcription factor that affects geneexpression (R. M. Evans, Science, 1988, 240, pp. 889-895). Other membersof the family of steroid receptors include the mineralocorticoid,progesterone, estrogen, and androgen receptors. In addition to theeffects mentioned above for glucocorticoids, hormones that act on thisreceptor family have a profound influence on body homeostasis, mineralmetabolism, the stress response, and development of sexualcharacteristics. Glucocorticoids, N. J. Goulding and R. J. Flowers(eds.), Boston: Birkhauser, 2001, is hereby incorporated by reference inits entirety to better describe the state of the art.

A molecular mechanism which accounts for the beneficialanti-inflammatory effects and the undesired side effects has beenproposed (e.g., S. Heck et al., EMBO J, 1994, 17, pp. 4087-4095; H. M.Reichardt et al., Cell, 1998, 93, pp. 531-541; F. Tronche et al., Curr.Opin. in Genetics and Dev., 1998, 8, pp. 532-538). Many of the metabolicand cardiovascular side effects are thought to be the result of aprocess called transactivation. In transactivation, the translocation ofthe ligand-bound glucocorticoid receptor to the nucleus is followed bybinding to glucocorticoid response elements (GREs) in the promoterregion of side effect-associated genes, for example, phosphoenolpyruvatecarboxy kinase (PEPCK), in the case of increased glucose production. Theresult is an increased transcription rate of these genes which isbelieved to result, ultimately, in the observed side effects. Theanti-inflammatory effects are thought to be due to a process calledtransrepression. In general, transrepression is a process independent ofDNA binding that results from inhibition of NF-kB and AP-1-mediatedpathways, leading to down regulation of many inflammatory and immunemediators. Additionally, it is believed that a number of the observedside effects may be due to the cross-reactivity of the currentlyavailable glucocorticoids with other steroid receptors, particularly themineralocorticoid and progesterone receptors.

Thus, it may be possible to discover ligands for the glucocorticoidreceptor that are highly selective and, upon binding, can dissociate thetransactivation and transrepression pathways, providing therapeuticagents with a reduced side effect profile. Assay systems to determineeffects on transactivation and transrepression have been described(e.g., C. M. Bamberger and H. M. Schulte, Eur. J. Clin. Invest., 2000,30 (suppl. 3), pp. 6-9). Selectivity for the glucocorticoid receptor maybe determined by comparing the binding affinity for this receptor withthat of other steroid family receptors including those mentioned above.

Glucocorticoids also stimulate the production of glucose in the liver bya process called gluconeogenesis and it is believed that this process ismediated by transactivation events. Increased glucose production canexacerbate type II diabetes, therefore a compound that selectivityinhibited glucocorticoid mediated glucose production may havetherapeutic utility in this indication (J. E. Freidman et al., J. Biol.Chem., 1997, 272, pp. 31475-31481).

Novel ligands for the glucocorticoid receptor have been described in thescientific and patent literature. For example, PCT InternationalPublication No. WO 99/33786 discloses triphenylpropanamide compoundswith potential use in treating inflammatory diseases. PCT InternationalPublication No. WO 00/66522 describes non-steroidal compounds asselective modulators of the glucocorticoid receptor potentially usefulin treating metabolic and inflammatory diseases. PCT InternationalPublication No. WO 99/41256 describes tetracyclic modulators of theglucocorticoid receptor potentially useful in treating immune,autoimmune, and inflammatory diseases. U.S. Pat. No. 5,688,810 describesvarious non-steroidal compounds as modulators of glucocorticoid andother steroid receptors. PCT International Publication No. WO 99/63976describes a non-steroidal, liver-selective glucocorticoid antagonistpotentially useful in the treatment of diabetes. PCT InternationalPublication No. WO 00/32584 discloses non-steroidal compounds havinganti-inflammatory activity with dissociation between anti-inflammatoryand metabolic effects. PCT International Publication No. WO 98/54159describes non-steroidal cyclically substituted acylanilides with mixedgestagen and androgen activity. U.S. Pat. No. 4,880,839 describesacylanilides having progestational activity and EP 253503 disclosesacylanilides with antiandrogenic properties. PCT InternationalPublication No. WO 97/27852 describes amides that are inhibitors offarnesyl-protein transferase.

A compound that is found to interact with the glucocorticoid receptor ina binding assay could be an agonist or an antagonist. The agonistproperties of the compound could be evaluated in the transactivation ortransrepression assays described above. Given the efficacy demonstratedby available glucocorticoid drugs in inflammatory and immune diseasesand their adverse side effects, there remains a need for novelglucocorticoid receptor agonists with selectivity over other members ofthe steroid receptor family and a dissociation of the transactivationand transrepression activities. Alternatively, the compound may be foundto have antagonist activity. As mentioned above, glucocorticoidsstimulate glucose production in the liver. Increased glucose productioninduced by glucocorticoid excess can exacerbate existing diabetes, ortrigger latent diabetes. Thus a ligand for the glucocorticoid receptorthat is found to be an antagonist may be useful, inter alia, fortreating or preventing diabetes.

SUMMARY OF THE INVENTION

The instant invention is directed to compounds of Formula (I)

wherein:

-   -   R¹ and R² are each independently hydrogen or C₁-C₅ alkyl, or R¹        and R² together with the carbon atom they are commonly attached        to form a C₃-C₆ ring;    -   R³ is a bond or C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl        group optionally independently substituted with one to three        substituent groups,        -   wherein each substituent group of R³ is independently C₃-C₈            cycloalkyl, aryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅            alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅            alkanoyloxy, aminocarbonyl, alkylaminocarbonyl,            dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅            alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅            alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅            alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, C₁-C₅            dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano,            trifluoromethyl, trifluoromethoxy, nitro, or amino wherein            the nitrogen atom is optionally independently mono- or            di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein            either nitrogen atom is optionally independently substituted            with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom            is optionally oxidized to a sulfoxide or sulfone,        -   wherein each substituent group of R³ is optionally            independently substituted with one to three substituent            groups selected from methyl, methoxy, halogen, hydroxy, oxo,            cyano, or amino;    -   R⁴ is hydrogen, C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈        cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅        alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅        alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy,        C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy,        C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅        alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, C₁-C₅        dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano,        trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro,        or amino wherein the nitrogen atom is optionally independently        mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either        nitrogen atom is optionally independently substituted with C₁-C₅        alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally        oxidized to a sulfoxide or sulfone;    -   R⁵ and R⁶ are each independently hydrogen, C₁-C₈ alkyl, C₂-C₈        alkenyl, or C₂-C₈ alkynyl group optionally independently        substituted with one to three substituent groups,        -   wherein each substituent group of R⁵ and R⁶ are            independently C₃-C₈ cycloalkyl, aryl, heteroaryl, C₁-C₅            alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy,            halogen, hydroxy, oxo, cyano, trifluoromethyl,            trifluoromethoxy, trifluoromethylthio, C₁-C₅ alkylthio            wherein the sulfur atom is optionally oxidized to a            sulfoxide or sulfone,        -   wherein each substituent group of R⁵ and R⁶ is optionally            independently substituted with one to three substituent            groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen,            hydroxy, oxo, cyano, amino, or trifluoromethyl, or    -   R⁵ and R⁶ together with the carbon atom they are commonly        attached to form a C₃-C₆ ring;    -   X is O, S, or amino wherein the nitrogen atom is optionally        independently mono- or di-substituted by C₁-C₅ alkyl or aryl and        the sulfur atom is optionally oxidized to a sulfoxide or        sulfone;    -   Y is an aryl or heteroaryl group, each optionally independently        substituted with one to three substituent groups,        -   wherein each substituent group of Y is independently C₁-C₅            alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, aryl,            C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy,            acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy,            aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,            aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅            dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅            alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅            alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen,            hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,            nitro, or amino wherein the nitrogen atom is optionally            independently mono- or di-substituted by C₁-C₅ alkyl or            aryl; or ureido wherein either nitrogen atom is optionally            independently substituted with C₁-C₅ alkyl; or C₁-C₅            alkylthio wherein the sulfur atom is optionally oxidized to            a sulfoxide or sulfone,        -   wherein each substituent group of Y is optionally            independently substituted with one to three substituent            groups selected from methyl, methoxy, halogen, hydroxy, oxo,            cyano, or amino;    -   n is 0, 1, 2, or 3,    -   or a tautomer, prodrug, solvate, or salt thereof,

A second aspect of the invention includes compounds of Formula (I),wherein:

-   -   R¹ and R² are each independently hydrogen or C₁-C₃ alkyl;    -   R³ is a bond or C₁-C₅ alkyl or C₂-C₅ alkenyl group optionally        independently substituted with one to two substituent groups,        -   wherein each substituent group of R³ is independently C₃-C₆            cycloalkyl, phenyl, methoxy, halogen, hydroxy, oxo, cyano,            trifluoromethyl, trifluoromethoxy, or C₁-C₅ alkylthio            wherein the sulfur atom is optionally oxidized to a            sulfoxide or sulfone,        -   wherein each substituent group of R³ is optionally            independently substituted with fluorine, chlorine, or            bromine;    -   R⁴ is hydrogen, C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈        cycloalkyl, phenyl, furanyl, thienyl, C₁-C₅ alkoxy, halogen,        hydroxy, cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₅        alkylthio wherein the sulfur atom is optionally oxidized to a        sulfoxide or sulfone;    -   R⁵ and R⁶ are each independently hydrogen, C₁-C₅ alkyl, C₂-C₅        alkenyl, or C₂-C₅ alkynyl;    -   X is O, NH, or S;    -   Y is a phenyl group independently substituted with one to two        substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,        halogen, hydroxy, cyano, trifluoromethyl, or trifluoromethoxy;    -   n is 1,    -   or a tautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (I)according to the second aspect of the invention, wherein R¹ and R² areeach methyl; R³ is a bond or C₁-C₅ alkyl or C₂-C₅ alkenyl group; R⁴ ishydrogen, C₃-C₆ cycloalkyl, phenyl, fluorine, or chlorine; R⁵ and R⁶ areeach independently hydrogen, methyl, or ethyl; X is O or S; Y is aphenyl group independently substituted with one to two substituentgroups selected from methoxy, fluorine, chlorine, or hydroxy, or atautomer, prodrug, solvate, or salt thereof.

Yet another aspect of the invention includes compounds of Formula (I),wherein R¹ and R² are each methyl; R³ is a bond; R⁴ is a C₃-C₅ alkyl orC₃-C₅ alkenyl group; R⁵ is hydrogen or methyl; R⁶ is hydrogen; X is O orS; and Y is a 2-methoxyphenyl, 2-methoxy-5-fluorophenyl, or2-chloro-3-hydroxyphenyl group, or a tautomer, prodrug, solvate, or saltthereof.

Another aspect of the invention includes compounds of Formula (I),wherein R¹ and R² are each methyl; R³ is a C²-C₄ alkyl group; R⁴ isphenyl group optionally monosubstituted with a fluorine or chlorinegroup; R⁵ is hydrogen or methyl; R⁶ is hydrogen; X is O or S; and Y is a2-methoxyphenyl, 2-methoxy-5-fluorophenyl, or 2-chloro-3-hydroxyphenylgroup, or a tautomer, prodrug, solvate, or salt thereof.

Still another aspect of the invention includes compounds of Formula (I),wherein R¹ and R² are each methyl; R³ is a C₁-C₃ alkyl group; R⁴ is acyclohexyl group; R⁵ is hydrogen or methyl; R⁶ is hydrogen; X is O or S;and Y is a 2-methoxyphenyl, 2-methoxy-5-fluorophenyl, or2-chloro-3-hydroxyphenyl group, or a tautomer, prodrug, solvate, or saltthereof.

The following are representative compounds of Formula (I) according tothe invention:

Compound Name Compound Structure [6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]phenylamine

(3,5-Dichlorophenyl)-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4- ylmethyl]amine

4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(3,5-Dichlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

Allyl-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine

[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl)propylamine

4-Allyloxymethyl-6-(2-methoxyphenyl)-2,2- dimethyl-1,2-dihydroquinoline

4-Benzylsulfanylmethyl-2,2dimethyl-6- phenyl-1,2-dihydroquinoline

4-Cyclopentylsulfanylmethyl-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

4-Benzylsulfanylmethyl-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-2,2-dimethyl-6-phenyl- 1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(2,6- dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

2-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]-N- methylacetamide

6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

3-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]propionic acid methyl ester

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2- methylbutylsulfanylmethyl)-1,2-dihydroquinoline

4-(4-tert-Butylphenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

4-Cyclohexylsulfanylmethyl-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3- methylbutylsulfanylmethyly-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(3-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(2-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

(E)-3-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]acrylic acid ethyl ester

4-(4-Methoxybenzylsulfanylmethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(prop-2-ene-1-sulfinylmethyl)-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4- (naphthalen-2-ylsulfanylmethyl)-1,2-dihydroquinoline

[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]acetic acid methyl ester

4-(4-Chlorophenylsulfanylmethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinolin-4-ylmethyl]-2-phenylacetamide

6-(2-Methoxyphenyl)-4-(4- methoxyphenylsulfanylmethyl)-2,2-dimethyl-1,2-dihydroquinoline

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinolin-4-ylmethyl]-N-methylbenzamide

4-Allylsulfanylmethyl-2,2-dimethyl-6-(2-nitrophenyl)-1,2-dihydroquinoline

4-Allylsulfanylmethyl-2,2-dimethyl-6-o-tolyl- 1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-dibenzofuran-4-yl-2,2-dimethyl-1,2-dihydroquinoline

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-N-methyl-2- phenylacetamide

4-(4-Chlorobenzylsulfanylmethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(2-fluorophenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(2-Fluorophenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-biphenyl-2-yl-2,2- dimethyl-1,2-dihydroquinoline

6-Biphenyl-2-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Thioacetic acid S-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl] ester

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline

4-(1-Allylsulfanylethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

2,2-Dimethyl-6-(2-methylsulfanylphenyl)-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(2,5- dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(2,5-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline

4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(3-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(3-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(4-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(4-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(3,4- dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(3,4-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline

6-(2,3-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(2,3- dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-6-(5-fluoro-2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl 4-phenethylsulfanylmethyl-1,2-dihydroquinoline

4-Allylsulfanylmethyl-2,2-dimethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline

2,2-Dimethyl-4-phenethylsulfanylmethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline

4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline

4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Cyclohexylmethoxyethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

2-Chloro-3-(2,2-dimethyl-4- phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol

3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol

6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1- [((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline

4-{1-[2-(2-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

4-Allylsulfanylmethyl-6-(5-isopropyl-2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(5-Isopropyl-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2- dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-(3-methylbut-2-enyloxy)ethyl]-1,2- dihydroquinoline

4-(1-Allyloxyethyl)-6-(5-fluoro-2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline

4-{1-[2-(3-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline

4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2- dihydroquinoline

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]1,2-dihydroquinoline

4-(1-Allyloxypropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Allyloxybutyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Allyloxy-3-phenylpropyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Allyloxybut-3-enyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Allyloxy-2-phenylethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(1-Allyloxy-2-methylpropyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-(Allyloxyphenylmethyl)-6-(2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Allyl-{1-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]ethyl}amine

Allyl-{1-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]ethyl}methylamine

4-(1-Allyloxyethyl)-6-(5-fluoro-2- methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

or a tautomer, prodrug, solvate, or salt thereof.

Preferred compounds of Formula (I) include the following:

-   4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline;-   4-Cyclohexylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3    -methylbutylsulfanylmethyl)-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline;-   4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;-   4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   6-(3-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline;-   4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline;-   4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-(1-Cyclohexylmethoxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   2-Chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol;-   3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-[((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-methylbut-2-enyloxy)ethyl]-1,2-dihydroquinoline;-   4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;-   4-{1-[2-(3-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;-   4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline;-   4-(1-Allyloxypropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-(1-Allyloxy-2-methylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;    and-   4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,    or a tautomer, prodrug, solvate, or salt thereof.

More preferred compounds of Formula (I) include the following:

-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline;-   4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;-   4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   2-Chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol;-   3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol;-   4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;-   6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;-   4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;-   6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline;    and-   4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,-   or a tautomer, prodrug, solvate, or salt thereof.

The invention also provides a method of making a compound of Formula (I)

where R³, R⁴, R⁵, R⁶, X, Y, and n are as defined in claim 1 and R¹ andR² are each methyl, the method comprising:

-   -   (a) reacting a 4-halonitrobenzene or 4-nitroaryltriflate of        Formula (II) with an arylboronic acid of Formula (III) in the        presence of a suitable palladium catalyst and base to form a        biaryl compound of Formula (IV)    -   (b) reducing the nitro group of the biaryl compound of        Formula (IV) by reaction with a suitable reducing agent to form        a compound of Formula (V)    -   (c) reacting the compound of Formula (V) with acetone in the        presence of iodine to form a compound of Formula (VI)    -   (d) reacting the compound of Formula (VI) with a suitable        brominating agent to form a compound of Formula (VII)    -   (e) reacting the compound of Formula (VII) with a nucleophile        R³R⁴XH_(m), where XH_(m) is NH₂, SH, or OH, in the presence of a        suitable base to form the compound of Formula (I)

In another aspect of the invention, the compounds according to theinvention are formulated into pharmaceutical compositions comprising aneffective amount, preferably a pharmaceutically effective amount, of acompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof, and a pharmaceutically acceptable excipient or carrier.

The invention also provides a method of modulating the glucocorticoidreceptor function in a patient, the method comprising administering tothe patient an effective amount of a compound according to the inventionor a tautomer, prodrug, solvate, or salt thereof.

The invention further provides a method of treating a disease-state orcondition mediated by the glucocorticoid receptor function in a patientin need of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

In addition, the invention also provides a method of treating adisease-state or condition selected from: type II diabetes, obesity,cardiovascular diseases, hypertension, arteriosclerosis, neurologicaldiseases, adrenal and pituitary tumors, and glaucoma, in a patient inneed of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

The invention provides a method of treating a disease characterized byinflammatory, allergic, or proliferative processes, in a patient in needof such treatment, the method comprising administering to the patient aneffective amount of a pharmaceutically acceptable compound according tothe invention or a tautomer, prodrug, solvate, or salt thereof. In apreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from: (i)lung diseases; (ii) rheumatic diseases or autoimmune diseases or jointdiseases; (iii) allergic diseases; (iv) vasculitis diseases; (v)dermatological diseases; (vi) renal diseases; (vii) hepatic diseases;(viii) gastrointestinal diseases; (ix) proctological diseases; (x) eyediseases; (xi) diseases of the ear, nose, and throat (ENT) area; (xii)neurological diseases; (xiii) blood diseases; (xiv) tumor diseases; (xv)endocrine diseases; (xvi) organ and tissue transplantations andgraft-versus-host diseases; (xvii) severe states of shock; (xviii)substitution therapy; and (xix) pain of inflammatory genesis. In anotherpreferred embodiment of the invention, the disease characterized byinflammatory, allergic, or proliferative processes is selected from:type I diabetes, osteoarthritis, Guillain-Barre syndrome, restenosisfollowing percutaneous transluminal coronary angioplasty, Alzheimerdisease, acute and chronic pain, atherosclerosis, reperfusion injury,bone resorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary to trauma,acute purulent meningitis, necrotizing enterocolitis, and syndromesassociated with hemodialysis, leukopheresis, and granulocytetransfusion.

The invention further provides methods of treating the disease-states orconditions mentioned above, in a patient in need of such treatment, themethods comprising sequentially or simultaneously administering to thepatient: (a) an effective amount of a pharmaceutically acceptablecompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof; and (b) a pharmaceutically acceptable glucocorticoid.

The invention further provides a method of assaying the glucocorticoidreceptor function in a sample, comprising: (a) contacting the samplewith a selected amount of a compound according to the invention or atautomer, prodrug, solvate, or salt thereof; and (b) detecting theamount of the compound according to the invention or a tautomer,prodrug, solvate, or salt thereof bound to glucocorticoid receptors inthe sample. In a preferred embodiment of the invention, the compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof is labeled with a detectable marker selected from: a radiolabel,fluorescent tag, a chemiluminescent tag, a chromophore, and a spinlabel.

The invention also provides a method of imaging the glucocorticoidreceptor distribution in a sample or patient, the method comprising: (a)contacting the sample or administering to a patient a compound accordingto the invention or a tautomer, prodrug, solvate, or salt thereof havinga detectable marker; (b) detecting the spatial distribution and amountof the compound according to the invention or a tautomer, prodrug,solvate, or salt thereof having a detectable marker bound toglucocorticoid receptors in the sample or patient using an imaging meansto obtain an image; and (c) displaying an image of the spatialdistribution and amount of the compound according to the invention or atautomer, prodrug, solvate, or salt thereof having a detectable markerbound to glucocorticoid receptors in the sample. In a preferredembodiment of the invention, the imaging means is selected from:radioscintigraphy, nuclear magnetic resonance imaging (MRI), computedtomography (CT scan), or positron emission tomography (PET).

The invention also provides a kit for the in vitro diagnosticdetermination of the glucocorticoid receptor function in a sample,comprising: (a) a diagnostically effective amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) instructions for use of the diagnostic kit.

Definition of Terms and Conventions Used

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification and appendedclaims, however, unless specified to the contrary, the following termshave the meaning indicated and the following conventions are adhered to.

A. Chemical Nomenclature, Terms, and Conventions

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁-C₁₀ alkylmeans an alkyl group or radical having 1 to 10 carbon atoms. The term“lower” applied to any carbon-containing group means a group containingfrom 1 to 8 carbon atoms, as appropriate to the group (i.e., a cyclicgroup must have at least 3 atoms to constitute a ring). In general, forgroups comprising two or more subgroups, the last named group is theradical attachment point, for example, “alkylaryl” means a monovalentradical of the formula Alk-Ar-, while “arylalkyl” means a monovalentradical of the formula Ar-Alk- (where Alk is an alkyl group and Ar is anaryl group). Furthermore, the use of a term designating a monovalentradical where a divalent radical is appropriate shall be construed todesignate the respective divalent radical and vice versa. Unlessotherwise specified, conventional definitions of terms control andconventional stable atom valences are presumed and achieved in allformulas and groups.

The terms “alkyl” or “alkyl group” mean a branched or straight-chainsaturated aliphatic hydrocarbon monovalent radical. This term isexemplified by groups such as methyl, ethyl, n-propyl, 1-methylethyl(isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), and thelike. It may be abbreviated “Alk”.

The terms “alkenyl” or “alkenyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon—carbon double bond. This term is exemplified by groups such asethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl, decenyl, and the like.

The terms “alkynyl” or “alkynyl group” mean a branched or straight-chainaliphatic hydrocarbon monovalent radical containing at least onecarbon—carbon triple bond. This term is exemplified by groups such asethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl,heptynyl, octynyl, decynyl, and the like.

The terms “alkylene” or “alkylene group” mean a branched orstraight-chain saturated aliphatic hydrocarbon divalent radical havingthe specified number of carbon atoms. This term is exemplified by groupssuch as methylene, ethylene, propylene, n-butylene, and the like, andmay alternatively and equivalently be denoted herein as -(alkyl)-.

The terms “alkenylene” or “alkenylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical having thespecified number of carbon atoms and at least one carbon—carbon doublebond. This term is exemplified by groups such as ethenylene,propenylene, n-butenylene, and the like, and may alternatively andequivalently be denoted herein as -(alkylenyl)-.

The terms “alkynylene” or “alkynylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical containing atleast one carbon-carbon triple bond. This term is exemplified by groupssuch as ethynylene, propynylene, n-butynylene, 2-butynylene,3-methylbutynylene, n-pentynylene, heptynylene, octynylene, decynylene,and the like, and may alternatively and equivalently be denoted hereinas -(alkynyl)-.

The terms “alkoxy” or “alkoxy group” mean a monovalent radical of theformula AlkO—, where Alk is an alkyl group. This term is exemplified bygroups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, pentoxy, and the like.

The terms “aryloxy”, “aryloxy group”, mean a monovalent radical of theformula ArO—, where Ar is aryl. This term is exemplified by groups suchas phenoxy, naphthoxy, and the like.

The terms “alkylcarbonyl”, “alkylcarbonyl group”, “alkanoyl”, or“alkanoyl group” mean a monovalent radical of the formula AlkC(O)—,where Alk is alkyl or hydrogen.

The terms “arylcarbonyl”, “arylcarbonyl group”, “aroyl” or “aroyl group”mean a monovalent radical of the formula ArC(O)—, where Ar is aryl.

The terms “acyl” or “acyl group” mean a monovalent radical of theformula RC(O)—, where R is a substituent selected from hydrogen or anorganic substituent. Exemplary substituents include alkyl, aryl,arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, andthe like. As such, the terms comprise alkylcarbonyl groups andarylcarbonyl groups.

The terms “acylamino” or “acylamino group” mean a monovalent radical ofthe formula RC(O)N(R)—, where each R is a substituent selected fromhydrogen or a substituent group.

The terms “alkoxycarbonyl” or “alkoxycarbonyl group” mean a monovalentradical of the formula AlkO—C(O)—, where Alk is alkyl. Exemplaryalkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,tert-butyloxycarbonyl, and the like.

The terms “aryloxycarbonyl” or “aryloxycarbonyl group” mean a monovalentradical of the formula ArO—C(O)—, where Ar is aryl.

The terms “alkylcarbonyloxy” or “alkylcarbonyloxy group” or“alkanoyloxy” or “alkanoyloxy group” mean a monovalent radical of theformula AlkC(O)O—, where Alk is alkyl.

The terms “arylcarbonyloxy” or “arylcarbonyloxy group” or “aroyloxy” or“aroyloxy group” mean a monovalent radical of the formula ArC(O)O—,where Ar is aryl.

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula R₂NC(O)O—, where each R isindependently hydrogen or lower alkyl.

The term “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula ROC(O)NH—, where R is lower alkyl.

The terms “alkylcarbonylamino” or “alkylcarbonylamino group” or“alkanoylamino” or “alkanoylamino groups” mean a monovalent radical ofthe formula AlkC(O)NH—, where Alk is alkyl. Exemplary alkylcarbonylaminogroups include acetamido (CH₃C(O)NH—).

The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxy group” meana monovalent radical of the formula AlkNHC(O)O—, where Alk is alkyl.

The terms “amino” or “amino group” mean an —NH₂ group.

The terms “alkylamino” or “alkylamino group” mean a monovalent radicalof the formula (Alk)NH—, where Alk is alkyl. Exemplary alkylamino groupsinclude methylamino, ethylamino, propylamino, butylamino,tert-butylamino, and the like.

The terms “dialkylamino” or “dialkylamino group” mean a monovalentradical of the formula (Alk)(Alk)N—, where each Alk is independentlyalkyl. Exemplary dialkylamino groups include dimethylamino,methylethylamino, diethylamino, dipropylamino, ethylpropylamino, and thelike.

The terms “substituted amino” or “substituted amino group” mean amonovalent radical of the formula —NR₂, where each R is independently asubstituent selected from hydrogen or the specified substituents (butwhere both Rs cannot be hydrogen). Exemplary substituents include alkyl,alkanoyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl,heteroarylalkyl, and the like.

The terms “alkoxycarbonylamino” or “alkoxycarbonylamino group” mean amonovalent radical of the formula AlkOC(O)NH—, where Alk is alkyl.

The terms “ureido” or “ureido group” mean a monovalent radical of theformula R₂NC(O)NH—, where each R is independently hydrogen or alkyl.

The terms “halogen” or “halogen group” mean a fluoro, chloro, bromo, oriodo group.

The term “halo” means one or more hydrogen atoms of the group arereplaced by halogen groups.

The terms “haloalkyl” or “haloalkyl group” mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical,wherein one or more hydrogen atoms thereof are each independentlyreplaced with halogen atoms. This term is exemplified by groups such aschloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl, 2-iodobutyl,1-chloro-2-bromo-3-fluoropentyl, and the like.

The terms “sulfanyl”, “sulfanyl group”, “thioether”, or “thioethergroup” mean a divalent radical of the formula —S—.

The terms “alkylthio” or “alkylthio group” mean a monovalent radical ofthe formula AlkS—, where Alk is alkyl. Exemplary groups includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and thelike.

The terms “arylthio” or “arylthio group” mean a monovalent radical ofthe formula ArS—, where Ar is aryl.

The terms “sulfinyl”, “sulfinyl group”, “thionyl”, or “thionyl group”mean a divalent radical of the formula —SO—.

The terms “sulfonyl” or “sulfonyl group” mean a divalent radical of theformula —SO₂—.

The terms “sulfonylamino” or “sulfonylamino group” mean a divalentradical of the formula —SO₂NR—, where R is a hydrogen or a substituentgroup.

The terms “aminosulfonyl” or “aminosulfonyl group” mean a monovalentradical of the formula NR₂SO₂—, where R is each independently a hydrogenor a substituent group.

The terms “carbocycle” or “carbocyclic group” mean a stable aliphatic 3-to 15-membered monocyclic or polycyclic monovalent or divalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecarbocycle may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. The term comprises cycloalkyl(including spiro cycloalkyl), cycloalkylene, cycloalkenyl,cycloalkenylene, cycloalkynyl, and cycloalkynylene, and the like.

The terms “cycloalkyl” or “cycloalkyl group” mean a stable aliphaticsaturated 3- to 15-membered monocyclic or polycyclic monovalent radicalconsisting solely of carbon and hydrogen atoms which may comprise one ormore fused or bridged ring(s), preferably a 5- to 7-membered monocyclicor 7- to 10-membered bicyclic ring. Unless otherwise specified, thecycloalkyl ring may be attached at any carbon atom which results in astable structure and, if substituted, may be substituted at any suitablecarbon atom which results in a stable structure. Exemplary cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornanyl, adamantyl,tetrahydronaphthyl (tetralin), 1-decalinyl, bicyclo[2.2.2]octanyl,1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and thelike.

The terms “cycloalkenyl” or “cycloalkenyl group” mean a stable aliphatic3- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon—carbon double bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 5- to 7-membered monocyclic or 7- to 10-membered bicyclicring. Unless otherwise specified, the cycloalkenyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkenyl groups includecyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl,cyclodecenyl, norbornenyl, 2-methylcyclopentenyl, 2-methylcyclooctenyl,and the like.

The terms “cycloalkynyl” or “cycloalkynyl group” mean a stable aliphatic8- to 15-membered monocyclic or polycyclic monovalent radical having atleast one carbon—carbon triple bond and consisting solely of carbon andhydrogen atoms which may comprise one or more fused or bridged ring(s),preferably a 8- to 10-membered monocyclic or 12- to 15-membered bicyclicring. Unless otherwise specified, the cycloalkynyl ring may be attachedat any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary cycloalkynyl groups include,cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl, and thelike.

The terms “cycloalkylene” or “cycloalkylene group” mean a stablesaturated aliphatic 3- to 15-membered monocyclic or polycyclic divalentradical consisting solely of carbon and hydrogen atoms which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring. Unlessotherwise specified, the cycloalkyl ring may be attached at any carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkylene groups include cyclopentylene, andthe like.

The terms “cycloalkenylene” or “cycloalkenylene group” mean a stablealiphatic 5- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon—carbon double bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to10-membered bicyclic ring. Unless otherwise specified, thecycloalkenylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkenylene groups include cyclopentenylene, cyclohexenylene,cycloheptenylene, cyclooctenylene, cyclononenylene, cyclodecenylene,norbornenylene, 2-methylcyclopentenylene, 2-methylcyclooctenylene, andthe like.

The terms “cycloalkynylene” or “cycloalkynylene group” mean a stablealiphatic 8- to 15-membered monocyclic or polycyclic divalent radicalhaving at least one carbon—carbon triple bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to15-membered bicyclic ring. Unless otherwise specified, thecycloalkynylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkynylene groups include cyclooctynylene, cyclononynylene,cyclodecynylene, 2-methylcyclooctynylene, and the like.

The terms “aryl” or “aryl group” mean an aromatic carbocyclic monovalentor divalent radical of from 6 to 14 carbon atoms having a single ring(e.g., phenyl or phenylene) or multiple condensed rings (e.g., naphthylor anthranyl). Unless otherwise specified, the aryl ring may be attachedat any suitable carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. Exemplary aryl groups include phenyl,naphthyl, anthryl, phenanthryl, indanyl, indenyl, biphenyl, and thelike. It may be abbreviated “Ar”.

The terms “heteroaryl” or “heteroaryl group” mean a stable aromatic 5-to 14-membered, monocyclic or polycyclic monovalent or divalent radicalwhich may comprise one or more fused or bridged ring(s), preferably a 5-to 7-membered monocyclic or 7- to 10-membered bicyclic radical, havingfrom one to four heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heteroarylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl,azaindolyl, dihydroindolyl, isoindolyl, benzofuranyl,dihydrobenzofuranyl, benzothienyl, dihydrobenzothienyl, indazolyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl,benzpyrazolyl, purinyl, quinolizinyl, quinolinyl, dihydroquinolinyl,tetrahydroquinolinyl, isoquinolinyl, dihydroisoquinolinyl,tetrahydroisoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.

The terms “heterocycle”, “heterocycle group”, “heterocyclyl”, or“heterocyclyl group” mean a stable non-aromatic 5- to 14-memberedmonocyclic or polycyclic, monovalent or divalent, ring which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring, having fromone to three heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heterocyclylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heterocycles include pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, and thelike.

The term “compounds of the invention” and equivalent expressions aremeant to embrace compounds of Formula (I) as herein described, includingthe tautomers, the prodrugs, the salts, particularly thepharmaceutically acceptable salts, and the solvates and hydratesthereof, where the context so permits. In general and preferably, thecompounds of the invention and the formulas designating the compounds ofthe invention are understood to only include the stable compoundsthereof and exclude unstable compounds, even if an unstable compoundmight be considered to be literally embraced by the compound formula.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts and solvates, where thecontext so permits. For the sake of clarity, particular instances whenthe context so permits are sometimes indicated in the text, but theseinstances are purely illustrative and it is not intended to excludeother instances when the context so permits.

The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” means that the aryl radical may or may not be substituted and thatthe description includes both substituted aryl radicals and arylradicals having no substitution.

The terms “stable compound” or “stable structure” mean a compound thatis sufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticor diagnostic agent. For example, a compound which would have a“dangling valency” or is a carbanion is not a compound contemplated bythe invention.

The term “substituted” means that any one or more hydrogens on an atomof a group or moiety, whether specifically designated or not, isreplaced with a selection from the indicated group of substituents,provided that the atom's normal valency is not exceeded and that thesubstitution results in a stable compound. If a bond to a substituent isshown to cross the bond connecting two atoms in a ring, then suchsubstituent may be bonded to any atom on the ring. When a substituent islisted without indicating the atom via which such substituent is bondedto the rest of the compound, then such substituent may be bonded via anyatom in such substituent. For example, when the substituent ispiperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise,such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in such piperazinyl,piperidinyl, or tetrazolyl group. Generally, when any substituent orgroup occurs more than one time in any constituent or compound, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0 to 2 R⁵, then such group is optionally substitutedwith up to two R⁵ groups and R⁵ at each occurrence is selectedindependently from the defined list of possible R⁵. Such combinations ofsubstituents and/or variables, however, are permissible only if suchcombinations result in stable compounds.

In a specific embodiment, the term “about” or “approximately” meanswithin 20%, preferably within 10%, and more preferably within 5% of agiven value or range.

The yield of each of the reactions described herein is expressed as apercentage of the theoretical yield.

B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions

The terms “prodrug” or “prodrug derivative” mean a covalently-bondedderivative or carrier of the parent compound or active drug substancewhich undergoes at least some biotransformation prior to exhibiting itspharmacological effect(s). In general, such prodrugs have metabolicallycleavable groups and are rapidly transformed in vivo to yield the parentcompound, for example, by hydrolysis in blood, and generally includeesters and amide analogs of the parent compounds. The prodrug isformulated with the objectives of improved chemical stability, improvedpatient acceptance and compliance, improved bioavailability, prolongedduration of action, improved organ selectivity, improved formulation(e.g., increased hydrosolubility), and/or decreased side effects (e.g.,toxicity). In general, prodrugs themselves have weak or no biologicalactivity and are stable under ordinary conditions. Prodrugs can bereadily prepared from the parent compounds using methods known in theart, such as those described in A Textbook of Drug Design andDevelopment, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach,1991, particularly Chapter 5: “Design and Applications of Prodrugs”;Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs:Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker,1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, AcademicPress, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry andDrug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as NovelDelivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975;Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier,1987, each of which is incorporated herein by reference in theirentireties.

The term “pharmaceutically acceptable prodrug” as used herein means aprodrug of a compound of the invention which is, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, commensurate with a reasonable benefit/riskratio, and effective for their intended use, as well as the zwitterionicforms, where possible.

The term “salt” means an ionic form of the parent compound or theproduct of the reaction between the parent compound with a suitable acidor base to make the acid salt or base salt of the parent compound. Saltsof the compounds of the present invention can be synthesized from theparent compounds which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts are prepared by reacting the freebase or acid parent compound with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents.

The term “pharmaceutically acceptable salt” means a salt of a compoundof the invention which is, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, generally water oroil-soluble or dispersible, and effective for their intended use. Theterm includes pharmaceutically-acceptable acid addition salts andpharmaceutically-acceptable base addition salts. As the compounds of thepresent invention are useful in both free base and salt form, inpractice, the use of the salt form amounts to use of the base form.Lists of suitable salts are found in, e.g., S. M. Birge et al., J.Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated byreference in its entirety.

The term “pharmaceutically-acceptable acid addition salt” means thosesalts which retain the biological effectiveness and properties of thefree bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoricacid, and the like, and organic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonicacid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid,glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylicacid, stearic acid, succinic acid, sulfanilic acid, tartaric acid,p-toluenesulfonic acid, undecanoic acid, and the like.

The term “pharmaceutically-acceptable base addition salt” means thosesalts which retain the biological effectiveness and properties of thefree acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

The term “solvate” means a physical association of a compound with oneor more solvent molecules or a complex of variable stoichiometry formedby a solute (for example, a compound of Formula (I)) and a solvent, forexample, water, ethanol, or acetic acid. This physical association mayinvolve varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances, the solvate will be capable ofisolation, for example, when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. Ingeneral, the solvents selected do not interfere with the biologicalactivity of the solute. Solvates encompasses both solution-phase andisolatable solvates. Representative solvates include hydrates,ethanolates, methanolates, and the like.

The term “hydrate” means a solvate wherein the solvent molecule(s)is/are H₂O.

The compounds of the present invention as discussed below include thefree base or acid thereof, their salts, solvates, and prodrugs and mayinclude oxidized sulfur atoms or quaternized nitrogen atoms in theirstructure, although not explicitly stated or shown, particularly thepharmaceutically acceptable forms thereof. Such forms, particularly thepharmaceutically acceptable forms, are intended to be embraced by theappended claims.

C. Isomer Terms and Conventions

The term “isomers” means compounds having the same number and kind ofatoms, and hence the same molecular weight, but differing with respectto the arrangement or configuration of the atoms in space. The termincludes stereoisomers and geometric isomers.

The terms “stereoisomer” or “optical isomer” mean a stable isomer thathas at least one chiral atom or restricted rotation giving rise toperpendicular dissymmetric planes (e.g., certain biphenyls, allenes, andspiro compounds) and can rotate plane-polarized light. Becauseasymmetric centers and other chemical structure exist in the compoundsof the invention which may give rise to stereoisomerism, the inventioncontemplates stereoisomers and mixtures thereof. The compounds of theinvention and their salts include asymmetric carbon atoms and maytherefore exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. Typically, such compounds will beprepared as a racemic mixture. If desired, however, such compounds canbe prepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Asdiscussed in more detail below, individual stereoisomers of compoundsare prepared by synthesis from optically active starting materialscontaining the desired chiral centers or by preparation of mixtures ofenantiomeric products followed by separation or resolution, such asconversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, use of chiral resolvingagents, or direct separation of the enantiomers on chiralchromatographic columns. Starting compounds of particularstereochemistry are either commercially available or are made by themethods described below and resolved by techniques well-known in theart.

The term “enantiomers” means a pair of stereoisomers that arenon-superimposable mirror images of each other.

The terms “diastereoisomers” or “diastereomers” mean optical isomerswhich are not mirror images of each other.

The terms “racemic mixture” or “racemate” mean a mixture containingequal parts of individual enantiomers.

The term “non-racemic mixture” means a mixture containing unequal partsof individual enantiomers.

The term “geometrical isomer” means a stable isomer which results fromrestricted freedom of rotation about double bonds (e.g., cis-2-buteneand trans-2-butene) or in a cyclic structure (e.g.,cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Becausecarbon—carbon double (olefinic) bonds, C═N double bonds, cyclicstructures, and the like may be present in the compounds of theinvention, the invention contemplates each of the various stablegeometric isomers and mixtures thereof resulting from the arrangement ofsubstituents around these double bonds and in these cyclic structures.The substituents and the isomers are designated using the cis/transconvention or using the E or Z system, wherein the term “E” means higherorder substituents on opposite sides of the double bond, and the term“Z” means higher order substituents on the same side of the double bond.A thorough discussion of E and Z isomerism is provided in J. March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thed., John Wiley & Sons, 1992, which is hereby incorporated by referencein its entirety. Several of the following examples represent single Eisomers, single Z isomers, and mixtures of E/Z isomers. Determination ofthe E and Z isomers can be done by analytical methods such as x-raycrystallography, ¹H NMR, and ¹³C NMR.

Some of the compounds of the invention can exist in more than onetautomeric form. As mentioned above, the compounds of the inventioninclude all such tautomers.

It is well-known in the art that the biological and pharmacologicalactivity of a compound is sensitive to the stereochemistry of thecompound. Thus, for example, enantiomers often exhibit strikinglydifferent biological activity including differences in pharmacokineticproperties, including metabolism, protein binding, and the like, andpharmacological properties, including the type of activity displayed,the degree of activity, toxicity, and the like. Thus, one skilled in theart will appreciate that one enantiomer may be more active or mayexhibit beneficial effects when enriched relative to the otherenantiomer or when separated from the other enantiomer. Additionally,one skilled in the art would know how to separate, enrich, orselectively prepare the enantiomers of the compounds of the inventionfrom this disclosure and the knowledge of the prior art.

Thus, although the racemic form of drug may be used, it is often lesseffective than administering an equal amount of enantiomerically puredrug; indeed, in some cases, one enantiomer may be pharmacologicallyinactive and would merely serve as a simple diluent. For example,although ibuprofen had been previously administered as a racemate, ithas been shown that only the S-isomer of ibuprofen is effective as ananti-inflammatory agent (in the case of ibuprofen, however, although theR-isomer is inactive, it is converted in vivo to the S-isomer, thus, therapidity of action of the racemic form of the drug is less than that ofthe pure S-isomer). Furthermore, the pharmacological activities ofenantiomers may have distinct biological activity. For example,S-penicillamine is a therapeutic agent for chronic arthritis, whileR-penicillamine is toxic. Indeed, some purified enantiomers haveadvantages over the racemates, as it has been reported that purifiedindividual isomers have faster transdermal penetration rates compared tothe racemic mixture. See U.S. Pat. Nos. 5,114,946 and 4,818,541.

Thus, if one enantiomer is pharmacologically more active, less toxic, orhas a preferred disposition in the body than the other enantiomer, itwould be therapeutically more beneficial to administer that enantiomerpreferentially. In this way, the patient undergoing treatment would beexposed to a lower total dose of the drug and to a lower dose of anenantiomer that is possibly toxic or an inhibitor of the otherenantiomer.

Preparation of pure enantiomers or mixtures of desired enantiomericexcess (ee) or enantiomeric purity are accomplished by one or more ofthe many methods of (a) separation or resolution of enantiomers, or (b)enantioselective synthesis known to those of skill in the art, or acombination thereof. These resolution methods generally rely on chiralrecognition and include, for example, chromatography using chiralstationary phases, enantioselective host-guest complexation, resolutionor synthesis using chiral auxiliaries, enantioselective synthesis,enzymatic and nonenzymatic kinetic resolution, or spontaneousenantioselective crystallization. Such methods are disclosed generallyin Chiral Separation Techniques: A Practical Approach (2nd Ed.), G.Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott,Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja,Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore,there are equally well-known methods for the quantitation ofenantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, andassignment of absolute configuration and conformation, for example, CDORD, X-ray crystallography, or NMR.

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or stereoisomers or racemic ornon-racemic mixtures, of a chemical structure or compound is intended,unless the specific stereochemistry or isomeric form is specificallyindicated in the compound name or structure.

D. Pharmaceutical Administration and Diagnostic and Treatment Terms andConventions

The term “patient” includes both human and non-human mammals.

The term “effective amount” means an amount of a compound according tothe invention which, in the context of which it is administered or used,is sufficient to achieve the desired effect or result. Depending on thecontext, the term effective amount may include or be synonymous with apharmaceutically effective amount or a diagnostically effective amount.

The terms “pharmaceutically effective amount” or “therapeuticallyeffective amount” means an amount of a compound according to theinvention which, when administered to a patient in need thereof, issufficient to effect treatment for disease-states, conditions, ordisorders for which the compounds have utility. Such an amount would besufficient to elicit the biological or medical response of a tissue,system, or patient that is sought by a researcher or clinician. Theamount of a compound of according to the invention which constitutes atherapeutically effective amount will vary depending on such factors asthe compound and its biological activity, the composition used foradministration, the time of administration, the route of administration,the rate of excretion of the compound, the duration of treatment, thetype of disease-state or disorder being treated and its severity, drugsused in combination with or coincidentally with the compounds of theinvention, and the age, body weight, general health, sex, and diet ofthe patient. Such a therapeutically effective amount can be determinedroutinely by one of ordinary skill in the art having regard to their ownknowledge, the prior art, and this disclosure.

The term “diagnostically effective amount” means an amount of a compoundaccording to the invention which, when used in a diagnostic method,apparatus, or assay, is sufficient to achieve the desired diagnosticeffect or the desired biological activity necessary for the diagnosticmethod, apparatus, or assay. Such an amount would be sufficient toelicit the biological or medical response in a diagnostic method,apparatus, or assay, which may include a biological or medical responsein a patient or in a in vitro or in vivo tissue or system, that issought by a researcher or clinician. The amount of a compound accordingto the invention which constitutes a diagnostically effective amountwill vary depending on such factors as the compound and its biologicalactivity, the diagnostic method, apparatus, or assay used, thecomposition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of administration, drugs and other compounds used incombination with or coincidentally with the compounds of the invention,and, if a patient is the subject of the diagnostic administration, theage, body weight, general health, sex, and diet of the patient. Such adiagnostically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, theprior art, and this disclosure.

The term “modulate” means the ability of a compound to alter thefunction of the glucocorticoid receptor by, for example, binding to andstimulating or inhibiting the glucocorticoid receptor functionalresponses.

The term “modulator” in the context of describing compounds according tothe invention means a compound that modulates the glucocorticoidreceptor function. As such, modulators include, but are not limited to,agonists, partial agonists, antagonists, and partial antagonists.

The term “agonist” in the context of describing compounds according tothe invention means a compound that, when bound to the glucocorticoidreceptor, enhances or increases the glucocorticoid receptor function. Assuch, agonists include partial agonists and full agonists.

The term “full agonist” in the context of describing compounds accordingto the invention means a compound that evokes the maximal stimulatoryresponse from the glucocorticoid receptor, even when there are spare(unoccupied) glucocorticoid receptors present.

The term “partial agonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal stimulatory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The term “antagonist” in the context of describing compounds accordingto the invention means a compound that directly or indirectly inhibitsor suppresses the glucocorticoid receptor function. As such, antagonistsinclude partial antagonists and full antagonists.

The term “full antagonist” in the context of describing compoundsaccording to the invention means a compound that evokes the maximalinhibitory response from the glucocorticoid receptor, even when thereare spare (unoccupied) glucocorticoid receptors present.

The term “partial antagonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal inhibitory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

The terms “treating” or “treatment” mean the treatment of adisease-state in a patient, and include:

-   -   (i) preventing the disease-state from occurring in a patient, in        particular, when such patient is genetically or otherwise        predisposed to the disease-state but has not yet been diagnosed        as having it;    -   (ii) inhibiting or ameliorating the disease-state in a patient,        i.e., arresting or slowing its development; or    -   (iii) relieving the disease-state in a patient, i.e., causing        regression or cure of the disease-state.

DETAILED DESCRIPTION OF THE INVENTION

General Synthetic Methods for Making Compounds of Formula (I)

The invention also provides processes for making compounds of Formula(I). In all schemes, unless specified otherwise, R¹ to R⁶, X, Y, and nin the formulas below shall have the meaning of R¹ to R⁶, X, Y, and n inthe Formula (I) of the invention described hereinabove. Intermediatesused in the preparation of compounds of the invention are eithercommercially available or readily prepared by methods known to thoseskilled in the art.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Experimental Examples section. Typically, reactionprogress may be monitored by thin layer chromatography (TLC), ifdesired, and intermediates and products may be purified bychromatography on silica gel and/or by recrystallization.

Compounds of Formula (I) may be prepared by the method outlined inScheme I.

As shown in Scheme I, a 4-halonitrobenzene such as 4-bromonitrobenzene(II) or a 4-nitroaryl triflate, undergoes a Suzuki reaction with anarylboronic acid (III) in the presence of a palladium catalyst such asPd(PPh₃)Cl₂ and a base, such as Na₂CO₃, to form a biaryl compound (IV).Reduction of biaryl compound (IV), for example, with a suitablecatalyst, such as Pd/C, in the presence of a hydrogen source, such asNH₄CO₂H, provides the aminobiaryl species (V). Skraup reaction (Org.Reactions, 1953, 7, 59) with a ketone such as acetone (shown), in thepresence of iodine provides the dihydroquinoline (VI) (R₁ and R₂ areboth CH₃ for a Skraup reaction with acetone). Bromination of thedihydroquinoline (VI) with a suitable brominating agent such asN-bromosuccinimide provides compound (VII). Reaction of compound (VII)with the desired nucleophile (for example, an amine, thiol, or alcohol)in the presence of a suitable base provides the desired compound ofFormula (I).

A procedure by which one may obtain compounds of Formula (I) in which Xis NH or NR′, where R′ is an alkyl group, is illustrated in Scheme II.

As illustrated in Scheme II, compound (VII) is reacted with sodium azidein a suitable solvent such as DMF to produce azide (VIII). The azidefunctionality of azide (VIII) is reduced by treatment with a reducingagent such as triphenylphosphine to produce amine (IX). Reaction ofamine (IX) with R⁴CO₂H under suitable coupling conditions, such as inthe presence of EDC and HOBT and a base such asN,N-diisopropylethylamine, produces amide (I), in this example where Xis NH and R³ is C(O). If one desires the corresponding compound withX=NR′, where R′ is an alkyl group or substituted alkyl group, one mayreact this product with R′Z, where Z is a halogen, preferably Br or I,in the presence of a base such as NaH to produce the desired compound ofFormula (I).

Scheme III illustrates a method by which one may obtain compounds ofFormula (I) in which X is O and R⁵ (or R⁶) is alkyl, alkenyl, oralkynyl.

As illustrated in Scheme III, the hydrogen on the ring nitrogen ofcompound (VI) is replaced by a protecting group such as the t-Boc-groupshown in X. Thus, treatment of compound (VI) with a base such as n-BuLifollowed by di-tert-butyl dicarbonate provides compound (X). Treatmentof compound (X) with a suitable oxidizing agent such as selenium dioxideprovides aldehyde (XI). This aldehyde (XI) is then reacted with aGrignard reagent R⁵MgX or R⁶MgX where X is halogen to provide alcohol(XII). Alkylation by treatment with R⁴R³Z where Z is halogen in thepresence of a base such as sodium bis(trimethylsilyl)amide, followed bydeprotection, for example, by treatment with trifluoroacetic acid for at-Boc-protecting group, provides the desired compound of Formula (I).

If desired, the hydroxy group on alcohol (XII) may be converted to aleaving group such as a methanesulfonyl ester and then be displaced byan alcohol, thiol, or amine to provide the desired compound of Formula(I) in which X is O, S, or NH, respectively. For example, as illustratedin Scheme IV, treatment of alcohol (XII) with methanesulfonyl chloridein the presence of a base such as triethylamine provides compound(XIII). Reaction of compound (XIII) with R⁴R³XH_(m) where XH_(m) is OH,SH, or NH₂, followed by deprotection as above provides the desiredcompound of Formula (I).

In a variation of the procedures described above, one may use the Skraupreaction described in Scheme I to prepare a dihydroquinoline substitutedin the 6-position with a group or a functionality that may be convertedto a group that will undergo a Suzuki reaction with an arylboronic acid.This is illustrated in Scheme V below. Thus, 4-ethoxyaniline (XIV)produces compound (XV) which may be converted by methods known in theart to the trifluoromethanesulfonyl ester (XVI). Alternatively,4-bromoaniline (XVII) provides compound (XVIII). Either of these mayundergo a Suzuki reaction with the desired Y—B(OH)₂ to produce compound(VI) which may then be used as described in the Schemes I to IV above toproduce desired compounds of Formula (I).

In yet another variation illustrated in Scheme V, compound (XVIII) maybe converted to a boronic acid derivative such as the4,4,5,5-tetramethyl-[1,3,2]-dioxaboran-2-yl derivative (XIX) shown. Thismay then undergo a Suzuki reaction with Y-Z where Z is a triflate or ahalogen, preferably Br or I, to produce the desired compound (VI).

Alternate procedures for preparation of the dihydroquinoline ring thatdo not require a Skraup reaction are known in the art, for example, inU.S. Pat. No. 6,001,846, which is hereby incorporated by reference, andmay be used to prepare compounds of Formula (I). Scheme VI illustrates aprocedure useful for preparing compounds of Formula (I) having R¹ and/orR² substituents other than methyl. As illustrated in Scheme VI, a2,4-dihaloaniline (XX), such as a 2,4-dibromoaniline, undergoes a Suzukireaction with an arylboronic acid (III) as described in Scheme I forintermediate (II), to produce halobiaryl compound (XXI). Thisintermediate (XXI) is then coupled with a 2-metalated propene (XXII) toproduce compound (XXIII). An example of a suitable coupling reaction isa Stille coupling, where compound (XXII) would be2-(tributylstannyl)propene. Subsequent reaction of compound (XXII) witha ketone bearing R¹ and R² in the presence of a catalyst such as borontrifluoride etherate or camphorsulfonic acid provides compound (VIa).This may then be carried forward as described for intermediate (VI) inScheme I to provide the desired compound of Formula (I).

In order that this invention be more fully understood, the followingexamples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way since, as recognizedby one skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used areeither commercially available or easily prepared from commerciallyavailable materials by those skilled in the art.

EXPERIMENTAL EXAMPLES Example 1 Synthesis of[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]phenylamine

A mixture of 20.8 g of 4-bromonitrobenzene and 17.2 g of 2-methoxyphenylboronic acid in 340 mL of ethylene glycol dimethyl ether and 170 mL of 2M sodium carbonate solution was purged with argon gas and then 3.6 g ofPd(PPh₃)₂Cl₂ was added under argon atmosphere. The reaction mixture washeated in a sealed flask at 120° C. overnight. The reaction mixture wascooled down to room temperature. The mixture was filtered throughdiatomaceous earth and the filtrate was diluted with water and theproduct was extracted three times with EtOAc. The organic layers werecombined, dried over magnesium sulfate (MgSO₄), and the solvent wasevaporated in vacuo. The residue was purified by flash chromatography toyield 17.1 g of 2-methoxy-4′-nitrobiphenyl as a solid.

A mixture of 52.4 g of 2-methoxy-4′-nitrobiphenyl and 76 g of ammoniumformate in 640 mL of methanol was treated with 6.4 g of 10% Pd/C at 0°C. The reaction mixture was allowed to stir at the same temperature forhalf an hour. The reaction was then warmed to room temperature and themixture was allowed to stir overnight. The reaction mixture was filteredthrough diatomaceous earth and the residue was rinsed with methanol. Themethanol was evaporated in vacuo and the remaining mixture was dissolvedin EtOAc and washed with water several times. The organic layer wasdried over magnesium sulfate. The solvent was evaporated in vacuo andyielded 49 g of 2-methoxy-4′-aminobiphenyl as a solid.

A mixture of 10 g of 2-methoxy-4′-aminobiphenyl, 4.4 g of iodine, 44 gof magnesium sulfate and 600 mL of acetone was heated in a sealed flaskat 120° C. overnight. The reaction mixture was cooled down to roomtemperature and filtered through diatomaceous earth. The residue wasrinsed with acetone and the solvent was evaporated in vacuo. The residuewas purified by flash chromatography to yield 2.4 g of6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline as a foam.

A mixture of 800 mg of6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline and 90 mL ofacetonitrile was treated with 510 mg of N-bromosuccinimide (NBS) at −20°C. for 2 minutes. The reaction was quenched with water and extractedwith EtOAc three times. The organic layers were combined and washed with10% aqueous sodium thiosulfate (Na₂S₂O₃) solution, water, and brine andthen dried over magnesium sulfate. The residue was purified by flashchromatography to yield 776 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as asolid.

A solution of 60 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline in 1mL of DMSO was treated with 46 mg of potassium carbonate and 17 μL ofaniline at room temperature. The resulting mixture was stirred at roomtemperature overnight. Then the mixture was quenched with water and theproduct was extracted into EtOAc. The organic layer was washed withwater and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel to give 9 mg of the title compound as a foam.

The following compounds were prepared by reacting4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline withthe appropriate amine, alcohol, or thiol using procedures analogous tothose described in Example 1.

(3,5-Dichlorophenyl)-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine2 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 32mg of potassium carbonate, and 20 mg of 3,5-dichloroaniline reacted togive 1.2 mg of the title compound as a foam.

4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline50 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 15 μL of allyl mercaptan reacted to give5 mg of the title compound as a foam.

4-(3,5-Dichlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline50 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 33 mg of 3,5-dichlorothiophenol reactedto give 15 mg of the title compound as a foam.

Allyl-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine54 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 28 μL of allyl amine reacted to give 8 mgof the title compound as a foam.

[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]propylamine44 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 30 μL of 1-propylamine reacted to give4.6 mg of the title compound as a foam.

4-Allyloxymethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline40 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 44μL of allyl alcohol, and 4 mL of 1 M solution of sodiumbis(trimethylsilyl)amide in THF reacted to give 4.5 mg of the titlecompound as a foam.

4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69mg of potassium carbonate, and 48 μL of cyclopentyl mercaptan reacted togive 7 mg of the title compound as a foam.

4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69mg of potassium carbonate, and 45 μL of furfuryl mercaptan reacted togive 9 mg of the title compound as a foam.

4-Benzylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69mg of potassium carbonate, and 52 μL of benzyl mercaptan reacted to give12 mg of the title compound as an oil.

4-Allylsulfanylmethyl-2,2-dimethyl-6-phenyl-1,2-dihydroquinoline 40 mgof 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,46 mg of potassium carbonate, and 44 μL of allyl mercaptan reacted togive 5 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 20 μL of 1-propanethiol reacted to give13 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 23 μL of thiophenol reacted to give 12 mgof the title compound as a foam.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 30 μL of benzeneethanethiol (phenethylmercaptan) reacted to give 15 mg of the title compound as a foam.

[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]aceticacid methyl ester 80 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 25 μL of methyl 3-mercaptopropionatereacted to give 14 mg of the title compound as a foam.

4-(4-tert-Butylphenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline60 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 25 μL of 4-tert-butylphenylthiophenolreacted to give 9 mg of the title compound as an oil.

4-Cyclohexylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline60 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 27 μL of cyclohexylmercaptan reacted togive 5 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3-methylbutylsulfanylmethyl)-1,2-dihydroquinoline60 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 28 μL of 3-methyl-1-butanethiol reactedto give 3 mg of the title compound as a foam.

4-(4-Methoxybenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 80 μL of 4-methoxy-α-toluenethiol reactedto give 19 mg of the title compound as an oil.

[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]aceticacid methyl ester 100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 52 μL of methyl thioglycolate reacted togive 4 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(naphthalen-2-ylsulfanylmethyl)-1,2-dihydroquinoline100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 42 mg of 2-naphthalenethiol reacted togive 8 mg of the title compound as an oil.

4-(4-Chlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 84 mg of 4-chloro benzenethiol reacted togive 10 mg of the title compound as a foam.

6-(2-Methoxyphenyl)-4-(4-methoxyphenylsulfanylmethyl)-2,2-dimethyl-1,2-dihydroquinoline100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 70 μL of 4-methoxy benzenethiol reactedto give 9 mg of the title compound as an oil.

4-(4-Chlorobenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline100 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80mg of potassium carbonate, and 76 μL of 4-chloro-α-toluenethiol reactedto give 8 mg of the title compound as an oil.

Thioacetic acidS-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]ester 776 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline in16 mL of methylene chloride was treated with 155 μL of thioacetic acidand 303 μL of triethylamine to give 100 mg of the title compound as afoam.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline60 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46mg of potassium carbonate, and 27 μL of 2-methyl-1-butanethiol reactedto give 4 mg of the title compound as an oil.

2-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]-N-methylacetamide50 mg of4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 15mg of N-methylmercaptoacetoamide, and 58 mg of potassium carbonatereacted to give 22 mg of the title compound as a foam.

Example 2 Synthesis of4-Allylsulfanylmethyl-6-(2,6-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

5 g of 4-bromonitrobenzene, 6.2 g of 2,6-dimethoxyphenyl boronic acid, 2mL of a 2 M sodium bicarbonate solution, and 800 mg ofbistriphenylphosphinyl palladium (II) chloride were reacted as describedin the first step of Example 1 to afford 4.5 g of the biphenylintermediate.

Following the procedure described in Example 1, 4 g of the abovebiphenyl, 6 g of ammonium formate, and 2 g of Pd/C gave 3.6 g of thecorresponding aniline, which was reacted with 1.3 g of iodine and 13 gof magnesium sulfate in acetone to produce 1.6 g of the desireddihydroquinoline. The above dihydroquinoline (1.3 g) reacted with 823 mgof NBS to provide the 4-bromomethyl derivative. Reaction with 0.4 mL ofallyl mercaptan afforded 720 mg of the title compound.

The following compounds were prepared beginning with the appropriatearyl boronic acid using procedures analogous to those described inExample 2.

4-Allylsulfanylmethyl-6-(3-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;and

4-Allylsulfanylmethyl-6-(2-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Example 3 Synthesis ofN-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide

To a round bottom flask equipped with a stir bar was added4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline (seeExample 1) (0.36 mmol), DMF (3.6 mL), and NaN₃ (0.54 mmol, 1.5 equiv).The reaction was stirred 48 hours under argon, then diluted with EtOAcand water, separated, and the aqueous phase was extracted with EtOAc.The combined organics were washed with water. The water wasback-extracted with EtOAc and the combined organics were washed withbrine and concentrated in vacuo. The residue was diluted with hexanesand a minimal amount of EtOAc and applied to a silica gel column. Flashchromatography, eluting with 0-30% EtOAc/hexanes provided 181 mg of4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline as abrown oil.

A round bottom flask equipped with a stir bar was charged with4-azidomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline(0.565 mmol) and THF (4.2 mL). The system was placed under argon, afterwhich PPh₃ (0.621 mmol, 1.1 equiv) and water (0.621 mmol, 1.1 equiv)were added. The reaction was stirred overnight at room temperature. Thecrude reaction mixture was diluted with ether and filtered throughdiatomaceous earth until no more precipitate formed. The diatomaceousearth was washed well with ether. The organic layer was acidified withconcentrated HCl affording a white fluffy precipitate which then oiledout. This layer was diluted with water and separated from the aqueouslayer. The aqueous layer was then neutralized with Na₂CO₃ and extractedwith methylene chloride. The organic extracts were combined andconcentrated in vacuo to afford 122 mg of4-aminomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline.

A round bottom flask equipped with a stir bar was charged with EDC(0.224 mmol, 1.1 equiv), HOBT (0.224 mmol, 1.1 equiv), benzoic acid(0.224 mmol, 1.1 equiv),4-aminomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline(0.204 mmol, 1 equiv) and 3.3 mL of methylene chloride. Diisopropylethyl amine (0.224 mmol, 1.1 equiv) was added last, the reaction wasplaced under argon, and stirred at room temperature overnight. The crudereaction mixture was transferred to a separatory funnel, diluted withEtOAc, and washed with 1 N HCl, aqueous saturated sodium bicarbonate(NaHCO₃) solution, and brine. The organics were concentrated in vacuo toafford a brown oil. The product was purified by column chromatographyusing silica gel eluting with a gradient of 10-50% EtOAc/hexanes. Theproduct fractions were pooled and concentrated in vacuo to afford 18 mgof the title compound as a yellow oil.

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-2-phenylacetamideThis compound was synthesized by the procedure described above, usingphenyl acetic acid in place of benzoic acid. The product fractions wereconcentrated in vacuo to afford 19 mg of the product as a yellow oil.

Example 4 Synthesis ofN-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-N-methylbenzamide

A round bottom flask equipped with a stir bar and under argon atmospherewas charged with NaH (60% in oil) (0.04 mmol, 1 equiv) and 1 mL of THF.Another vessel containingN-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide(Example 3) was diluted with THF and this solution was added to the NaHsolution. Lastly, MeI (0.06 mmol, 1.5 equiv) was added and the reactionwas stirred 5 hours under argon. The reaction was quenched with waterand extracted with EtOAc. The combined organics were subsequently washedwith brine and concentrated in vacuo. The residue was taken up inmethylene chloride and adsorbed onto silica gel and flashchromatographed using 25% EtOAc/hexanes to elute product. The productfractions were pooled and concentrated in vacuo to afford 7.2 mg of thetitle compound as a oil.

N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-N-methyl-2-phenylacetamideThis compound was synthesized by the procedure described above, startingwithN-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-2-phenylacetamideto afford 7.7 mg of product as an oil.

Example 5 Synthesis of4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline

A mixture of 2.4 g of6-(2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (see Example 1)in 35 mL of CH₂Cl₂ was cooled down to −78° C. To this mixture, 13.1 mLof 1.6 M n-BuLi in hexane was added dropwise. The mixture was warmed to0° C. and 2.9 g of (di-tert-butyl)carbonate was added. The mixture wasallowed to stir at 0° C. for 1 hour. The reaction was then worked up byadding water and extracting with EtOAc three times. The organic layerswere combined, washed sequentially with 1 N HCl, water, saturatedaqueous sodium bicarbonate solution, water, saturated aqueous NaClsolution, dried over magnesium sulfate, and the solvent evaporated invacuo. The residue was purified by flash chromatography to yield 1.4 gof 6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester as a solid.

A mixture of 1.6 g of6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester, 20 mL of 1,4-dioxane, and 1.4 g of selenium dioxidewas refluxed for half an hour. Another 1.4 g portion of selenium dioxidewas added. The reaction was allowed to reflux for 6 hours. The reactionmixture was then filtered through diatomaceous earth and the residue wasrinsed with EtOAc. The solvent was evaporated in vacuo and the residuewas purified by flash chromatography to yield 1 g of4-formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester as a solid.

A mixture of 1 g of[6-(2-methoxyphenyl)-2,2,4-trimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester] in 15 mL of THF was cooled down to −78° C. To thismixture, 1.3 mL of 3 M methylmagnesium bromide in diethyl ether wasadded dropwise. Ten minutes later, another 1.25 mL of 3 Mmethylmagnesium bromide in diethyl ether was added. The reaction wasquenched 2 hours later with saturated aqueous ammonium chloride (NH₄Cl)solution and the product was extracted with EtOAc three times. Theorganic layers were combined, washed sequentially with 0.5 N HCl, water,saturated aqueous sodium bicarbonate solution, water, and brine, anddried over magnesium sulfate. The residue was purified by flashchromatography to yield 708 mg of4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester as a light yellow solid.

A mixture of 70 mg of4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester in 2 mL of DMSO was treated with 0.22 mL of 1.0 Msodium bis(trimethylsilyl)amide and 29 mg of crotyl bromide at roomtemperature. The reaction mixture was allowed to stir at roomtemperature overnight. The reaction was worked up by adding water andextracted with EtOAc three times. The organic layers were combined,washed sequentially with saturated aqueous sodium bicarbonate solution,water, and brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyto yield 58 mg of4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester as a solid.

A mixture of 58 mg of[4-{1-[((E)-but-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester in 2 mL of methylene chloride was treated with0.05 mL of 99% trifluoroacetic acid (TFA) at room temperature. Thereaction mixture was allowed to stir at the same temperature for 1 hour.TLC showed starting material was still remaining so another 0.05 mL ofTFA was added. Ten minutes later, the reaction was quenched with waterand extracted with EtOAc three times. The organic layers were combined,washed sequentially with water, saturated aqueous sodium bicarbonate,water, brine, dried with magnesium sulfate, and the solvent evaporatedin vacuo. The residue was purified by flash chromatography to yield 28mg of the title compound as an oil.

The following compounds were prepared using the appropriate alkylbromide in place of crotyl bromide and appropriate Grignard reagent inplace of methylmagnesium bromide, where applicable, using proceduresanalogous to those described in Example 5.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (116 mg) in 2 mL of DMSO was treated with 334 μLof 1 M solution of sodium bis(trimethylsilyl)amide in THF and 52 μL of1-bromo-3-phenylpropane to give the alkylated product, which was thendeprotected (as above) to yield 31 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution ofsodium bis(trimethylsilyl)amide in THF and 50 mg of cinnamyl bromide togive the alkylated product, which was deprotected to yield 5.8 mg of thetitle compound as a foam.

4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution ofsodium bis(trimethylsilyl)amide in THF and 49 mg of 2-cyclohexylethylbromide to give the alkylated product, which was deprotected to yield 31mg of title compound as an oil.

4-(1-Cyclohexylmethoxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 255 μL of 1 M solution ofsodium bis(trimethylsilyl)amide in THF and 45 mg of cyclohexylmethylbromide to give the alkylated product, which was deprotected to yield 8mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-[((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 220 μL of 1 M solution ofsodium bis(trimethylsilyl)amide in THF and 26 μL of 1-bromo-2-pentene togive the alkylated product, which was deprotected to yield 30 mg of thetitle compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-methylbut-2-enyloxy)ethyl]-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (96 mg) was treated with 450 μL of 1 M solution ofsodium bis(trimethylsilyl)amide in THF and 50 μL of4-bromo-2-methyl-2-butene to give the alkylated product, which wasdeprotected to yield 14.5 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline4-(1-Hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (100 mg) was treated with 360 μL of 1 M solutionof sodium bis(trimethylsilyl)amide in THF and 45 μL of phenethyl bromideto give the alkylated product, which was deprotected to yield 62 mg ofthe title compound as an oil.

4-(1-Allyloxypropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (50 mg) in THF was treated with 0.1 mL of 2 M ethylmagnesium chloride to give the alcohol, which was alkylated by allyliodide and then deprotected to yield 10 mg of the title compound as anoil.

4-(1-Allyloxybutyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (70 mg) in THF was treated with 0.133 mL of 2 Mpropylmagnesium bromide to give the alcohol, which was alkylated byallyl iodide and then deprotected to yield 26 mg of the title compoundas an oil.

4-(1-Allyloxy-3-phenylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (70 mg) in THF was treated with 0.267 mL of 1 Mphenethylmagnesium bromide to give the alcohol, which was alkylated byallyl iodide and then deprotected to yield 31 mg of the title compoundas an oil.

4-(1-Allyloxybut-3-enyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (70 mg) in THF was treated with 0.267 mL of 1 Mallylmagnesium bromide to give the alcohol, which was alkylated by allyliodide and then deprotected to yield 46 mg of the title compound as anoil.

4-(1-Allyloxy-2-phenylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (70 mg) in THF was treated with 0.133 mL of 2 Mbenzylmagnesium bromide to give the alcohol, which was alkylated byallyl iodide and then deprotected to yield 3.5 mg of the title compoundas an oil.

4-(1-Allyloxy-2-methylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (120 mg) in THF was treated with 0.31 mL of 15%solution of isopropylmagnesium bromide to give the alcohol, which wasalkylated by allyl iodide and then deprotected to yield 17 mg of thetitle compound as an oil.

4-(Allyloxyphenylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Formyl-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylic acidtert-butyl ester (50 mg) in THF was treated with 0.19 mL of 1 Mphenylmagnesium bromide to give the alcohol, which was alkylated byallyl iodide and then deprotected to yield 30 mg of the title compoundas an oil.

Example 6 Synthesis of4-{1-[2-(2-bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

A mixture of 300 mg of4-(1-hydroxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (see Example 5) and 10 mL of methylene chloridewas cooled to 0° C. To this mixture, 0.060 mL of methanesulfonylchloride and 0.204 mL of triethylamine were added. The reaction mixturewas allowed to stir at the same temperature for 30 minutes. The reactionwas worked up by adding water, and the product was extracted with EtOActhree times. The organic layers were combined, washed sequentially withsaturated aqueous ammonium chloride solution, saturated aqueous sodiumbicarbonate solution, water, and brine, and dried over magnesiumsulfate. The solvent was evaporated in vacuo to give 344 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester as a solid, which was used for the next couplingreaction without further purification.

A mixture of 0.037 mL of 2-bromophenethyl alcohol and 1 mL of DMSO wastreated with 0.277 mL of 1.0 M sodium bis(trimethylsilyl)amide, then 86mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester in 1 mL DMSO was added at room temperature. Thereaction mixture was allowed to stir at room temperature overnight. TLCshowed starting material was consumed. The reaction was quenched withwater and the product was extracted with EtOAc three times. The organiclayers were combined, washed sequentially with saturated aqueousammonium chloride solution, saturated aqueous sodium bicarbonatesolution, water, and brine, dried over magnesium sulfate, and thesolvent evaporated in vacuo. The residue was purified by flashchromatography to yield 37 mg of4-{1-[2-(2-bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester as an oil.

37 mg of the above tert-butyl ester was deprotected with TFA to yield 11mg of the title compound as a foam.

The following compounds were prepared by using the appropriate alcoholor thiol in place of 2-bromophenethyl alcohol, using proceduresanalogous to those described in Example 6.

4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline-4-(1-Methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 33 μL allyl alcohol and12 mg of sodium hydride in DMF to give alkylated product, which wasdeprotected to yield 9 mg of the title compound as a foam.

4-{1-[2-(2-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-(1-Methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester (70 mg) was treated with 28 μL of2-chlorophenethyl alcohol and 245 μL of 1 M solution of sodiumbis(trimethylsilyl)amide in THF to give alkylated product, which wasdeprotected to yield 6 mg of the title compound as a foam.

4-{1-[2-(3-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline3-Chlorophenethyl alcohol (50 μL) was treated with 369 μL of 1 Msolution of sodium bis(trimethylsilyl)amide in THF and 120 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product, which was deprotectedto yield 32 mg of the title compound as an oil.

4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline4-Chlorophenethyl alcohol (37 μL) was treated with 277 μL of 1 Msolution of sodium bis(trimethylsilyl)amide in THF and 86 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product, which was deprotectedto yield 14 mg of the title compound as a foam.

4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline3-Bromophenethyl alcohol (37 μL) was treated with 277 μL of 1 M solutionof sodium bis(trimethylsilyl)amide in THF and 86 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product, which was deprotectedto yield 13.6 mg of the title compound as a foam.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline3-Buten-2-ol was treated (24 μL) with 277 μL of 1 M solution of sodiumbis(trimethylsilyl)amide in THF and 86 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product, which was deprotectedto yield 4 mg of the title compound as an oil.

6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline2-phenylethanethiol (19 μL) was treated 58 mg of potassium carbonate and60 mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product, which was deprotectedto yield 14 mg of the title compound as an oil.

4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolineAllyl mercaptan (10 μL) was treated 58 mg of potassium carbonate and 60mg of4-(1-methanesulfonyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-2H-quinoline-1-carboxylicacid tert-butyl ester to give alkylated product which was deprotected toyield 9 mg of the title compound as an oil.

Example 7 Synthesis of4-Allylsulfanylmethyl-2,2-dimethyl-6-thiophen-3-yl-1,2-dihydroquinoline

A solution of 31 g of 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline in300 mL of dichloromethane was treated with 30 mL of boron tribromidedropwise at −78° C. After the addition of boron tribromide, the coolingbath was removed and the reaction mixture was allowed to warm to roomtemperature. The resulting mixture was stirred at room temperature for 2hours. The reaction mixture was then poured into crushed ice and the pHwas adjusted to 9 with sodium bicarbonate. The product was the extractedinto EtOAc. The organic solution was washed with water and brine, driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas purified by filtering through a short plug of silica gel elutingwith 25% EtOAc in hexanes solution to give 12.4 g of2,2,4-trimethyl-1,2-dihydroquinolin-6-ol as a light brown solid.

A solution of 12.4 g of 2,2,4-trimethyl-1,2-dihydroquinilin-6-ol and 20mL of triethyl amine in 360 mL of dichloromethane was treated with 12.1mL of trifluoromethanesulfonic anhydride, added dropwise at 0° C. Theresulting mixture was allowed to warm to room temperature and stirred atthat temperature for 1 hour. The reaction mixture was quenched withsaturated sodium bicarbonate solution and the product was extracted intoethyl ether. The ethyl ether layer was washed with water and brine,dried over magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel (eluting with20% EtOAc in hexanes) to give 19.3 g of trifluoromethanesulfonic acid2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester as a light brown solid.

To a dry 50 mL round bottom flask charged with a mixture oftrifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester (0.50 g, 1.56 mmol), Pd(OAc)₂ (0.035 g, 0.156 mmol),di-tert-butylbiphenylphosphine (DTBBPP) (0.093 g, 0.312 mmol), and KF(0.27 g, 4.67 mmol) suspended in THF (5 mL), was added3-thiopheneboronic acid (0.30 g, 2.33 mmol). The flask was evacuated andflushed three times with argon and the reaction mixture was allowed tostir at room temperature for 2 days. The reaction mixture was filteredthrough diatomaceous earth and diluted with EtOAc (50 mL). The mixturewas sequentially washed with water (10 mL), NaOH (1.0 M, 10 mL), andbrine (10 mL). The organic phase was dried over sodium sulfate (Na₂SO₄),filtered, and concentrated in vacuo. The crude residue was purified bychromatography (silica gel, 30% dichloromethane in hexanes) to give2,2,4-trimethyl-6-thiophen-3-yl-1,2-dihydroquinoline (0.128 g, 32%).

2,2,4-Trimethyl-6-thiophen-3-yl-1,2-dihydroquinoline was brominated withNBS using the procedure described in Example 1 and then coupled withallyl mercaptan using the procedure described in Example 2 to provide 22mg of the title compound as a oil.

The following compounds were prepared by using the appropriate aryl orheteroaryl boronic acid and mercaptan, using procedures analogous tothose described in Example 7.

Allylsulfanylmethyl-6-(2-fluorophenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-fluorophenyl boronic acid. Bromination andcoupling reaction with allyl mercaptan gave 36 mg of the title compound.

4-Benzylsulfanylmethyl-2,2-dimethyl-6-phenyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with phenyl boronic acid. Bromination and couplingreaction with 2-phenylethanethiol gave 7 mg of the title compound.

6-(2-Fluorophenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-fluorophenyl boronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 72 mg of the titlecompound.

4-Allylsulfanylmethyl-2,2-dimethyl-6-o-tolyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-methylphenyl boronic acid. Bromination andcoupling reaction with allyl mercaptan gave 35 mg of4-allylsulfanylmethyl-2,2-dimethyl-6-o-tolyl-1,2-dihydroquinoline.

4-Allylsulfanylmethyl-6-dibenzofuran-4-yl-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 4-dibenzofuranboronic acid. Bromination andcoupling reaction with allyl mercaptan gave 52 mg of the title compound.

4-Allylsulfanylmethyl-6-biphenyl-2-yl-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-biphenylboronic acid. Bromination and couplingreaction with allyl mercaptan gave 13 mg of the title compound.

6-Biphenyl-2-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-biphenylboronic acid. Bromination and couplingreaction with 2-phenylethanethiol gave 57 mg of the title compound.

2,2-Dimethyl-6-(2-methylsulfanylphenyl)-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-(methylthio)phenylboronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 59 mg of the titlecompound.

4-Allylsulfanylmethyl-6-(2,5-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2,5-dimethoxyphenylbornic acid. Bromination andcoupling reaction with allyl mercaptan gave 20 mg of the title compound.

6-(2,5-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2,5-dimethoxyphenylboronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 43 mg of the titlecompound.

4-Allylsulfanylmethyl-6-(3-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 3-methoxyphenylboronic acid. Bromination andcoupling reaction with allyl mercaptan gave 20 mg of the title compound.

6-(3-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 3-methoxyphenylboronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 21 mg of the titlecompound.

4-Allylsulfanylmethyl-6-(4-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 4-methoxyphenylboronic acid. Bromination andcoupling reaction with allyl mercaptan gave 10 mg of the title compound.

6-(4-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 4-methoxyphenylboronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 15 mg of the titlecompound.

4-Allylsulfanylmethyl-6-(3,4-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 3,4-dimethoxyphenylboronic acid. Bromination andcoupling reaction with allyl mercaptan gave 10 mg of the title compound.

6-(3,4-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 3,4-dimethoxyphenylboronic acid. Bromination andcoupling reaction with 2-phenylethanethiol gave 10 mg the titlecompound.

4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

(Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 5-fluoro-2-methoxyphenylboronic acid. Brominationand coupling reaction with allyl mercaptan gave 17 mg of the titlecompound.

6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 5-fluoro-2-methoxyphenylboronic acid. Brominationand coupling reaction with 2-phenylethanethiol gave 20 mg of the titlecompound.

4-Allylsulfanylmethyl-2,2-dimethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-trifluoromethylphenylboronic acid. Brominationand coupling reaction with allyl mercaptan gave 23 mg of the titlecompound.

2,2-Dimethyl-4-phenethylsulfanylmethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 2-trifluoromethylphenylboronic acid. Brominationand coupling reaction with 2-phenylethanethiol gave 49 mg of the titlecompound.

4-Allylsulfanylmethyl-6-(5-isopropyl-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 5-isopropyl-2-methoxyphenylboronic acid.Bromination and coupling reaction with allyl mercaptan gave 25 mg of thetitle compound.

6-(5-Isopropyl-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester was coupled with 5-isopropyl-2-methoxyphenylboronic acid.Bromination and coupling reaction with 2-phenylethanethiol gave 30 mg ofthe title compound.

Example 8 Synthesis of4-Allylsulfanylmethyl-6-(2-nitrophenyl)-2,2-dimethyl-1,2-dihydroquinoline

4-Bromoaniline (50 g, 0.290 mol), magnesium sulfate (250 g, 2 mol),iodine (2.5 g, 0.01 mol) and catechol (2.24 g, 0.020 mol) were combinedin acetone (750 mL) in a sealed-tube reaction flask. The reaction vesselwas placed in a pre-equilibrated oil bath set at 125° C. and stirredovernight. The reaction mixture was then cooled to room temperature,filtered over a pad of diatomaceous earth, and concentrated in vacuo.Chromatography on silica gel provided6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline as tan colored crystals (21g, 27% yield).

6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline was coupled with2-nitrophenylboronic acid using the procedure described in Example 7 fortrifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-ylester. The resulting intermediate was brominated with NBS, followed bythe coupling reaction with allyl mercaptan as described in Example 7, toprovide 15 mg of the title compound as an oil.

6-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline200 mg of 6-bromo-2,2,4-trimethyl-1,2-dihydroquinoline, 160 mg of3,4-(methylenedioxy)phenylboronic acid, 30 mg of PdCl₂(dppf), and 234 mgof KOAc was reacted to afford 80 mg of the coupled intermediate.Reaction of this intermediate (80 mg) with 53 mg of NBS, followed by thecoupling reaction with 0.043 mL of allyl mercaptan as described inExample 7, afforded 15 mg of the title compound.

Example 9 Synthesis of6-(2,3-dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline

To a solution of N,N,N′,N′-tetramethylethylenediamine (6.1 mL, 40.5mmol) in diethylether (100 mL) at 0° C. was added dropwise n-BuLi (26mL, 42 mmol). After 30 minutes, the reaction mixture was cooled to −78°C. and 1,2-dimethoxybenzene was added dropwise. The reaction was stirredfor 3 hours at that temperature. After the addition of trimethylboronate (9.7 mL, 87 mmol), the cold bath was removed and the reactionstirred for 18 hours. After cooling to 0° C., 150 mL of 2 M aqueous HClsolution was added and the mixture was stirred for 3 hours. The mixturewas extracted with three 20 mL portions of EtOAc, dried over magnesiumsulfate, filtered, and concentrated in vacuo to afford 2,3-dimethoxyphenyl boronic acid as white crystals (1 g, 37% yield).

6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (256 mg, 1.02 mmol)(Example 8) and 2,3-dimethoxyphenyl boronic acid (370 mg, 2.03 mmol)were combined in DMSO (2 mL). 2 M K₃PO₄ (1 mL) was added, followed byPdCl₂(dppf) (50 mg). The contents were placed in a microwave reactionvessel assembly and irradiated at 120° C. for 15 minutes. The reactionwas cooled to room temperature. Purification of the crude product bychromatography afforded6-(2,3-dimethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (190 mg,61%) as a white solid.

Bromination with NBS followed by the coupling reaction with2-phenylethanethiol using the procedures described in Example 7 provided45 mg of the title compound as an oil.

4-Allylsulfanylmethyl-6-(2,3-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline

This compound was synthesized by following the general proceduredescribed in Example 9.4-bromomethyl-6-(2,3-dimethoxyphe-2,2-dimethyl-1,2-dihydroquinoline wascoupled with 0.2 mL of allyl mercaptan to give 35 mg of the titlecompound as an oil.

Example 10 Synthesis of2-chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline-6-yl)phenol

To a suspension of 2-amino-3-nitrophenol (10 g, 65 mmol) in concentratedHCl (10 mL) at 0° C., sodium nitrite (5.1 g, 73.3 mmol) in water (60 mL)was added dropwise. After stirring for 30 minutes at 0° C., CuCl (12.8g, 130 mmol) in 10% H₂SO₄ (3 mL) was added and the reaction was stirredfor 18 hours. The heterogeneous mixture was filtered and washed withwater. The filtrate was extracted three times with 70 mL portions ofEtOAc. Evaporation of EtOAc extractions afforded 7 grams (62% yield) ofpure 2-chloro-3-nitrophenol. 2-Chloro-3-nitrophenol (6 g, 35 mmol) wasdissolved in methanol (100 mL) and treated with ammonium chloride (9.4g, 175.7 mmol) and zinc dust (46 g, 702.8 mmol). The resulting mixturewas refluxed for one hour. After filtration and evaporation,2-chloro-3-aminophenol was collected (4.5 g, 90% yield) as a purplesolid. To a suspension of 2-chloro-3-aminophenol (4.5 g, 31 mmol) inconcentrated HCl (10 mL) at 0° C. was added dropwise sodium nitrite (2.5g, 35 mmol) in water (50 mL). After stirring for 30 minutes at 0° C., KI(10.4 g, 63 mmol) in 10% H₂SO₄ (3 mL) was added dropwise. The reactionwas stirred at room temperature for 2 hours, then filtered, extractedwith EtOAc, and concentrated in vacuo to afford 2-chloro-3-iodophenol asa dark purple solid (6 g, 75% yield).

6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline (2.3 g, 9.2 mmol) (Example8) and bis(pinacol)diborane (4.2 g, 16.5 mmol) were combined in DMSO (2mL). KOAc (2.7 g, 27.4 mmol) was added, followed by PdCl₂(dppf) (100mg). The contents were placed into a microwave reaction vessel assemblyand irradiated at 120° C. for 15 minutes. After cooling to roomtemperature, purification by chromatography afforded2,2,4-trimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydroquinoline(2.3 g, 84% yield) as a white crystalline solid.

2,2,4-Trimethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydroquinoline(308 mg) and 393 mg of 2-chloro-3-iodophenol were coupled using of 100mg of PdCl₂(dppf) and 300 mg of KOAc to give 250 mg of2-chloro-3-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)-phenol. Using theprocedures described in Example 7, this (85 mg) was reacted with NBS togive 56 mg of3-(4-bromomethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol.The product (50 mg) was coupled with 0.04 mL of 2-phenylethanethiol togive 40 mg of the title compound as an oil.

3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol

This product was prepared as described above, except 0.023 mL of allylmercaptan was used in the final coupling step to give 32 mg of the titlecompound as an oil.

Assessment of Biological Properties

Compounds of the invention were evaluated for binding to the steroidreceptor by a fluorescence polarization competitive binding assay.Detailed descriptions for preparation of recombinant glucocorticoidreceptor (GR) complex used in the assay is described in U.S. PatentApplication Publication No. 2003/0,017,503, filed May 20, 2002, and thecorresponding U.S. provisional application No. 60/291,877, filed May 18,2001, each of which is incorporated herein by reference in its entirety.Preparation of the tetramethyl rhodamine (TAMRA)-labeled dexamethasoneprobe was accomplished using a standard literature procedure (M. Pons etal., J. Steroid Biochem., 1985, 22, pp. 267-273).

A. Glucocorticoid Receptor Competitive Binding Assay

Step 1. Characterization of the Fluorescent Probe

The wavelengths for maximum excitation and emission of the fluorescentprobe should first be measured. An example of such a probe is rhodamine(TAMRA)-labeled dexamethasone.

The affinity of the probe for the steroid receptor was then determinedin a titration experiment. The fluorescence polarization value of theprobe in assay buffer was measured on an SLM-8100 fluorometer using theexcitation and emission maximum values described above. Aliquots ofexpression vector lysate were added and fluorescence polarization wasmeasured after each addition until no further change in polarizationvalue was observed. Non-linear least squares regression analysis wasused to calculate the dissociation constant of the probe from thepolarization values obtained for lysate binding to the probe.

Step 2. Screening for Inhibitors of Probe Binding

This assay uses fluorescence polarization (FP) to quantitate the abilityof test compounds to compete with tetramethyl rhodamine (TAMRA)-labeleddexamethasone for binding to a human glucocorticoid receptor (GR)complex prepared from an insect expression system. The assay buffer was:10 mM TES, 50 mM KCl, 20 mM Na₂MoO₄.2H₂O, 1.5 mM EDTA, 0.04% w/v CHAPS,10% v/v glycerol, 1 mM dithiothreitol, pH 7.4. Test compounds weredissolved to 1 mM in neat DMSO and then further diluted to 10× assayconcentration in assay buffer supplemented with 10% v/v DMSO. Testcompounds were serially diluted at 10× assay concentrations in 10%DMSO-containing buffer in 96-well polypropylene plates. Binding reactionmixtures were prepared in 96-well black Dynex microtiter plates bysequential addition of the following assay components to each well: 15μL of 10× test compound solution, 85 μL of GR-containing baculoviruslysate diluted 1:170 in assay buffer, and 50 μL of 15 nM TAMRA-labeleddexamethasone. Positive controls were reaction mixtures containing notest compound; negative controls (blanks) were reaction mixturescontaining 0.7 μM to 2 μM dexamethasone.

The binding reactions were incubated for 1 hour at room temperature andthen read for fluorescence polarization in the LJL Analyst set to 550 nmexcitation and 580 nm emission, with the Rhodamine 561 dichroic mirrorinstalled. IC₅₀ values were determined by iterative non-linear curvefitting of the FP signal data to a 4-parameter logistic equation.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor binding to the progesterone receptor (PR), estrogen receptor (ER),and mineralocorticoid receptors to evaluate the compound's selectivityfor GR. The protocols for PR and MR are identical to the above GRmethod, with the following exceptions: PR insect cell lysate is diluted1:7.1 and MR lysate diluted 1:9.4. PR probe is TAMRA-labeledmifepristone, used at a final concentration of 5 nM in the assay, andthe negative controls (blanks) were reactions containing mifepristone at0.7 μM to 2 μM.

The ER protocol is similar to the above protocols, but uses PanVera kitreceptor, fluorescein-labeled probe. The assay components are made inthe same volumes as above, to produce final assay concentrations for ERof 15 nM and ES2 probe of 1 nM. In addition, the component order ofaddition is modified from the above assays: probe is added to the platefirst, followed by receptor and test compound. The plates are read inthe LJL Analyst set to 485 nm excitation and 530 nm emission, with theFluorescein 505 dichroic mirror installed.

Compounds found to bind to the glucocorticoid receptor may be evaluatedfor dissociation of transactivation and transrepression by assays citedin the Background of the Invention (C. M. Bamberger and H. M. Schulte,Eur. J. Clin. Invest., 2000, 30 (suppl. 3) 6-9) or by the assaysdescribed below.

B. Glucocorticoid Receptor Cell Assays

1. Induction of Aromatase in Fibroblasts (Cell Assay forTransactivation)

Dexamethasone, a synthetic ligand to the glucocorticoid receptor (GR),induces expression of aromatase in human foreskin fibroblast cells. Theactivity of aromatase is measured by the conversion of testosterone toestradiol in culture media. Compounds that exhibit binding to GR areevaluated for their ability to induce aromatase activity in humanforeskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429, designationCCD112SK) are plated on 96 well plates at 50,000 cells per well 5 daysbefore use, in Iscove's Modified Dulbecco's Media (GibcoBRL LifeTechnologies Cat No. 12440-053) supplemented with 10% charcoal filteredFBS (Clonetech Cat No. SH30068) and Gentamycin (GibcoBRL LifeTechnologies Cat. No. 15710-064). On the day of the experiment, themedia in the wells is replaced with fresh media. Cells are treated withtest compounds to final concentrations of 10⁻⁵ M to 10⁻⁸ M, andtestosterone to a final concentration of 300 ng/mL. Each well has atotal volume of 100 μL. Samples are made in duplicates. Control wellsinclude: (a) wells that receive testosterone only, and (b) wells thatreceive testosterone plus 2 μM of dexamethasone to provide maximuminduction of aromatase. Plates are incubated at 37° C. overnight (15 to18 hours), and supernatants are harvested at the end of incubation.Estradiol in the supernatant is measured using ELISA kits for estradiol(made by ALPCO, obtained from American Laboratory Products Cat. No.020-DR-2693) according to the manufacture's instruction. The amount ofestradiol is inversely proportional to the ELISA signals in each well.The extent of aromatase induction by test compounds is expressed as arelative percentage to dexamethasone. EC₅₀ values of test compounds arederived by non-linear curve fitting.

2. Inhibition of IL-6 Production in Fibroblasts (Cell Assay forTransrepression)

Human foreskin fibroblast cells produce IL-6 in response to stimulationby pro-inflammatory cytokine IL-1. This inflammatory response, asmeasured by the production of IL-6, can be effectively inhibited bydexamethasone, a synthetic ligand to the glucocorticoid receptor (GR).Compounds that exhibit binding to GR are evaluated for their ability toinhibit IL-6 production in human foreskin fibroblasts.

Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429) are plated on96 well plates at 5,000 cells per well the day before use, in Iscove'sModified Dulbecco's Media (GibcoBRL Life Technologies Cat. No.12440-053) supplemented with 10% charcoal filtered FBS (Clonetech Cat.No. SH30068) and Gentamycin (GibcoBRL Life Technologies Cat. No.15710-064). On the next day, media in the wells is replaced with freshmedia. Cells are treated with IL-1 (rhIL-1α, R&D Systems Cat. No.200-LA) to a final concentration of 1 ng/mL, and with test compounds tofinal concentrations of 10⁻⁵ M to 10⁻⁸ M, in a total volume of 200 μLper well. Samples are done in duplicates. Background control wells donot receive test compounds or IL-1. Positive control wells receive IL-1only and represent maximum (or 100%) amount of IL-6 production. Platesare incubated at 37° C. overnight (15 to 18 hours), and supernatants areharvested at the end of incubation. IL-6 levels in the supernatants aredetermined by the ELISA kits for IL-6 (MedSystems Diagnostics GmbH,Vienna, Austria, Cat. No. BMS213TEN) according to manufacture'sinstructions. The extent of inhibition of IL-6 by test compounds isexpressed in percentage relative to positive controls. IC₅₀ values oftest compounds are derived by non-linear curve fitting.

Evaluation of agonist or antagonist activity of compounds binding to theglucocorticoid receptor may be determined by any of the assays.

3. Modulation of Tyrosine Aminotransferase (TAT) Induction in RatHepatoma Cells

Testing of compounds for agonist or antagonist activity in induction oftyrosine aminotransferase (TAT) in rat hepatoma cells.

H4-II-E-C3 cells were incubated overnight in 96 well plates (20,000cells/100 μL/well) in MEM medium containing 10% heat inactivated FBS and1% nonessential amino acids. On the next day, cells were stimulated withthe indicated concentrations of dexamethasone or test compound(dissolved in DMSO, final DMSO concentration 0.2%) for 18 hours. Controlcells were treated with 0.2% DMSO. After 18 hours, the cells were lysedin a buffer containing 0.1% Triton X-100 and the TAT activity wasmeasured in a photometric assay using tyrosine and alpha-ketoglutarateas substrates.

For measuring antagonist activity, the hepatoma cells werepre-stimulated by addition of dexamethasone (concentration ranges from3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the test compound was applied tothe cells. The steroidal non-selective GR/PR antagonist mifepristone wasused as control.

4. Modulation of MMTV-Luc Induction in HeLa Cells

Testing of compounds for agonist or antagonist activity in stimulationof MMTV-(mouse mammary tumor virus) promoter in HeLa cells.

HeLa cells were stably co-transfected with the pHHLuc-plasmid containinga fragment of the MMTV-LTR (−200 to +100 relative to the transcriptionstart site) cloned in front of the luciferase gene (Norden, 1988) andthe pcDNA3.1 plasmid (Invitrogen) constitutively expressing theresistance for the selective antibiotic GENETICIN®. Clones with bestinduction of the MMTV-promoter were selected and used for furtherexperiments.

Cells were cultured overnight in DMEM medium without phenol red,supplemented with 3% CCS (charcoal treated calf serum) and thentransferred to 96 well plates (15,000 cells/100 μL/well). On the nextday, activation of the MMTV-promoter was stimulated by addition of testcompound or dexamethasone dissolved in DMSO (final concentration 0.2%).Control cells were treated with DMSO only. After 18 hours, the cellswere lysed with cell lysis reagent (Promega, Cat. No. E1531), luciferaseassay reagent (Promega, Cat. No. E1501) was added and the glowluminescence was measured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the MMTV-promoter was pre-stimulatedby adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the testcompound was applied to the cells. The steroidal non-selective GR/PRantagonist mifepristone was used as control.

5. Modulation of IL-8 Production in U93 7 Cells

Testing of compounds for agonist or antagonist activity in GR-mediatedinhibition of LPS-induced IL-8 secretion in U-937 cells.

U-937 cells were incubated for 2 to 4 days in RPM11640 medium containing10% CCS (charcoal treated calf serum). The cells were transferred to 96well plates (40,000 cells/100 μL/well) and stimulated with 1 μg/mL LPS(dissolved in PBS) in the presence or absence of dexamethasone or testcompound (dissolved in DMSO, final concentration 0.2%). Control cellswere treated with 0.2% DMSO. After 18 hours, the IL-8 concentration inthe cell supernatant was measured by ELISA, using the “OptEIA human IL-8set” (Pharmingen, Cat. No. 2654KI).

For measuring antagonist activity, the LPS-induced IL-8 secretion wasinhibited by adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortly beforethe test compound was applied to the cells. The steroidal non-selectiveGR/PR antagonist mifepristone was used as control.

6. Modulation of ICAM-Luc Expression in HeLa Cells

Testing of compounds for agonist or antagonist activity in inhibition ofTNF-alpha-induced activation of the ICAM-promoter in HeLa cells.

HeLa cells were stably co-transfected with a plasmid containing a 1.3 kbfragment of the human ICAM-promoter (−1353 to −9 relative to thetranscription start site, Ledebur and Parks, 1995) cloned in front ofthe luciferase gene and the pcDNA3.1 plasmid (Invitrogen) whichconstitutively expresses the resistance for the antibiotic GENETICIN®.Clones with best induction of the ICAM-promoter were selected and usedfor further experiments. Cells were transferred to 96 well plates(15,000 cells/100 μL/well) in DMEM medium supplemented with 3% CCS. Onthe following day the activation of the ICAM-promoter was induced byaddition of 10 ng/mL recombinant TNF-alpha (R&D System, Cat. No.210-TA). Simultaneously the cells were treated with the test compound ordexamethasone (dissolved in DMSO, final concentration 0.2%). Controlcells were treated with DMSO only. After 18 hours, the cells were lysedwith cell lysis reagent (Promega, Cat. No. E1531), luciferase assayreagent (Promega, Cat. No. E1501) was added and glow luminescence wasmeasured using a luminometer (BMG, Offenburg).

For measuring antagonist activity, the TNF-alpha-induced activation ofthe ICAM-promoter was inhibited by adding dexamethasone (3×10⁻⁹ M to3×10⁻⁸ M) shortly before the test compound was applied to the cells. Thesteroidal non-selective GR/PR antagonist mifepristone was used ascontrol.

In general, the preferred potency range in the above assays is between0.1 nM and 10 μM, the more preferred potency range is 0.1 nM to 1 μM,and the most preferred potency range is 0.1 nM to 100 nM.

Representative compounds of the invention have been tested and haveshown activity as modulators of the glucocorticoid receptor function inone or more of the above assays. For example, the following compounds ofthe invention of Formula (I) have demonstrated potent activity asantagonists in cellular assays:

-   -   4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;        and    -   4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline.

In addition, the following compound of the invention of Formula (I) hasbeen tested and has shown activity as an agonist of the glucocorticoidreceptor function in one or more of the above assays:

-   -   4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline.

The invention also provides methods of modulating the glucocorticoidreceptor function in a patient comprising administering to the patient acompound according to the invention. If the purpose of modulating theglucocorticoid receptor function in a patient is to treat adisease-state or condition, the administration preferably comprises atherapeutically or pharmaceutically effective amount of apharmaceutically acceptable compound according to the invention. If thepurpose of modulating the glucocorticoid receptor function in a patientis for a diagnostic or other purpose (e.g., to determine the patient'ssuitability for therapy or sensitivity to various sub-therapeutic dosesof the compounds according to the invention), the administrationpreferably comprises an effective amount of a compound according to theinvention, that is, the amount necessary to obtain the desired effect ordegree of modulation.

Methods of Therapeutic Use

As pointed out above, the compounds of the invention are useful inmodulating the glucocorticoid receptor function. In doing so, thesecompounds have therapeutic use in treating disease-states and conditionsmediated by the glucocorticoid receptor function or that would benefitfrom modulation of the glucocorticoid receptor function.

As the compounds of the invention modulate the glucocorticoid receptorfunction, they have very useful anti-inflammatory and antiallergic,immune-suppressive, and anti-proliferative activity and they can be usedin patients as drugs, particularly in the form of pharmaceuticalcompositions as set forth below, for the treatment of disease-states andconditions.

The agonist compounds according to the invention can be used in patientsas drugs for the treatment of the following disease-states orindications that are accompanied by inflammatory, allergic, and/orproliferative processes:

-   -   (i) Lung diseases: chronic, obstructive lung diseases of any        genesis, particularly bronchial asthma and chronic obstructive        pulmonary disease (COPD); adult respiratory distress syndrome        (ARDS); bronchiectasis; bronchitis of various genesis; all forms        of restrictive lung diseases, particularly allergic alveolitis;        all forms of lung edema, particularly toxic lung edema; all        forms of interstitial lung diseases of any genesis, e.g.,        radiation pneumonitis; and sarcoidosis and granulomatoses,        particularly Boeck disease.    -   (ii) Rheumatic diseases or autoimmune diseases or joint        diseases: all forms of rheumatic diseases, especially rheumatoid        arthritis, acute rheumatic fever, and polymyalgia rheumatica;        reactive arthritis; rheumatic soft tissue diseases; inflammatory        soft tissue diseases of other genesis; arthritic symptoms in        degenerative joint diseases (arthroses); traumatic arthritis;        collagenoses of any genesis, e.g., systemic lupus erythematosus,        scleroderma, polymyositis, dermatomyositis, Sjögren syndrome,        Still disease, and Felty syndrome;    -   (iii) Allergic diseases: all forms of allergic reactions, e.g.,        angioneurotic edema, hay fever, insect bites, allergic reactions        to drugs, blood derivatives, contrast agents, etc., anaphylactic        shock (anaphylaxis), urticaria, angioneurotic edema, and contact        dermatitis;    -   (iv) Vasculitis diseases: panarteritis nodosa, polyarteritis        nodosa, arteritis temporalis, Wegner granulomatosis, giant cell        arthritis, and erythema nodosum;    -   (v) Dermatological diseases: atopic dermatitis, particularly in        children; psoriasis; pityriasis rubra pilaris; erythematous        diseases triggered by various noxa, e.g., rays, chemicals,        burns, etc.; bullous dermatoses; diseases of the lichenoid        complex; pruritus (e.g., of allergic genesis); seborrheic        dermatitis; rosacea; pemphigus vulgaris; erythema multiforme        exudativum; balanitis; vulvitis; hair loss, such as occurs in        alopecia areata; and cutaneous T cell lymphomas;    -   (vi) Renal diseases: nephrotic syndrome; and all types of        nephritis, e.g., glomerulonephritis;    -   (vii) Hepatic diseases: acute liver cell disintegration; acute        hepatitis of various genesis, e.g., viral, toxic, drug-induced;        and chronically aggressive and/or chronically intermittent        hepatitis;    -   (viii) Gastrointestinal diseases: inflammatory bowel diseases,        e.g., regional enteritis (Crohn disease), colitis ulcerosa;        gastritis; peptic esophagitis (refluxoesophagitis); and        gastroenteritis of other genesis, e.g., nontropical sprue;    -   (ix) Proctological diseases: anal eczema; fissures; hemorrhoids;        and idiopathic proctitis;    -   (x) Eye diseases: allergic keratitis, uveitis, or iritis;        conjunctivitis; blepharitis; neuritis nervi optici; choroiditis;        and sympathetic ophthalmia;    -   (xi) Diseases of the ear, nose, and throat (ENT) area: allergic        rhinitis or hay fever; otitis externa, e.g., caused by contact        eczema, infection, etc.; and otitis media;    -   (xii) Neurological diseases: brain edema, particularly        tumor-related brain edema; multiple sclerosis; acute        encephalomyelitis; meningitis; acute spinal cord injury; stroke;        and various forms of seizures, e.g., nodding spasms;    -   (xiii) Blood diseases: acquired hemolytic anemia; and idiopathic        thrombocytopenia;    -   (xiv) Tumor diseases: acute lymphatic leukemia; malignant        lymphoma; lymphogranulomatoses; lymphosarcoma; extensive        metastases, particularly in mammary, bronchial, and prostatic        carcinoma;    -   (xv) Endocrine diseases: endocrine ophthalmopathy; endocrine        orbitopathia; thyrotoxic crisis; Thyroiditis de Quervain;        Hashimoto thyroiditis; Morbus Basedow; granulomatous        thyroiditis; struma lymphomatosa; and Grave disease;    -   (xvi) Organ and tissue transplantations and graft-versus-host        diseases;    -   (xvii) Severe states of shock, e.g., septic shock, anaphylactic        shock, and systemic inflammatory response syndrome (SIRS);    -   (xviii) Substitution therapy in: congenital primary adrenal        insufficiency, e.g., adrenogenital syndrome; acquired primary        adrenal insufficiency, e.g., Addison disease, autoimmune        adrenalitis, post-infection, tumors, metastases, etc.;        congenital secondary adrenal insufficiency, e.g., congenital        hypopituitarism; and acquired secondary adrenal insufficiency,        e.g., post-infection, tumors, metastases, etc.;    -   (xix) Pain of inflammatory genesis, e.g., lumbago; and    -   (xx) various other disease-states or conditions including type I        diabetes (insulin-dependent diabetes), osteoarthritis,        Guillain-Barre syndrome, restenosis following percutaneous        transluminal coronary angioplasty, Alzheimer disease, acute and        chronic pain, atherosclerosis, reperfusion injury, bone        resorption diseases, congestive heart failure, myocardial        infarction, thermal injury, multiple organ injury secondary to        trauma, acute purulent meningitis, necrotizing enterocolitis and        syndromes associated with hemodialysis, leukopheresis, and        granulocyte transfusion.

In addition, the compounds according to the invention can be used forthe treatment of any other disease-states or conditions not mentionedabove which have been treated, are treated, or will be treated withsynthetic glucocorticoids (see, e.g., H. J. Hatz, Glucocorticoide:Immunologische Grundlagen, Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Fundamentals, Pharmacology, andTherapeutic Guidelines], Stuttgart: Verlagsgesellschaft mbH, 1998, whichis hereby incorporated by reference in its entirety). Most or all of theindications (i) through (xx) mentioned above are described in detail inH. J. Hatz, Glucocorticoide: Immunologische Grundlagen, Pharmakologieund Therapierichtlinien. Furthermore, the compounds of the invention canalso be used to treat disorders other than those listed above ormentioned or discussed herein, including in the Background of theInvention.

The antagonist compounds according to the invention, whether fullantagonists or partial antagonists, can be used in patients as drugs forthe treatment of the following disease-states or indications, withoutlimitation: type II diabetes (non-insulin-dependent diabetes); obesity;cardiovascular diseases; hypertension; arteriosclerosis; neurologicaldiseases, such as psychosis and depression; adrenal and pituitarytumors; glaucoma; and Cushing syndrome based on an ACTH secreting tumorlike pituitary adenoma. In particular, the compounds of the inventionare useful for treating obesity and all disease-states and indicationsrelated to a deregulated fatty acids metabolism such as hypertension,atherosclerosis, and other cardiovascular diseases. Using the compoundsof the invention that are GR antagonists, it should be possible toantagonize both the carbohydrate metabolism and fatty acids metabolism.Thus, the antagonist compounds of the invention are useful in treatingall disease-states and conditions that involve increased carbohydrate,protein, and lipid metabolism and would include disease-states andconditions leading to catabolism like muscle frailty (as an example ofprotein metabolism).

Methods of Diagnostic Use

The compounds of the invention may also be used in diagnosticapplications and for commercial and other purposes as standards incompetitive binding assays. In such uses, the compounds of the inventionmay be used in the form of the compounds themselves or they may bemodified by attaching a radioisotope, luminescence, fluorescent label orthe like in order to obtain a radioisotope, luminescence, or fluorescentprobe, as would be known by one of skill in the art and as outlined inHandbook of Fluorescent Probes and Research Chemicals, 6th Edition, R.P. Haugland (ed.), Eugene: Molecular Probes, 1996; Fluorescence andLuminescence Probes for Biological Activity, W. T. Mason (ed.), SanDiego: Academic Press, 1993; Receptor-Ligand Interaction, A PracticalApproach, E. C. Hulme (ed.), Oxford: IRL Press, 1992, each of which ishereby incorporated by reference in their entireties.

General Administration and Pharmaceutical Compositions

When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

In particular, the compounds of the invention are useful in combinationwith glucocorticoids or corticosteroids. As pointed out above, standardtherapy for a variety of immune and inflammatory disorders includesadministration of corticosteroids, which have the ability to suppressimmunologic and inflammatory responses. (A. P. Truhan et al., Annals ofAllergy, 1989, 62, pp. 375-391; J. D. Baxter, Hospital Practice, 1992,27, pp. 111-134; R. P. Kimberly, Curr. Opin. Rheumatol., 1992, 4, pp.325-331; M. H. Weisman, Curr. Opin. Rheumatol., 1995, 7, pp. 183-190; W.Sterry, Arch. Dermatol. Res., 1992, 284 (Suppl.), pp. S27-S29). Whiletherapeutically beneficial, however, the use of corticosteroids isassociated with a number of side effects, ranging from mild to possiblylife threatening, especially with prolonged and/or high dose steroidusage. Accordingly, methods and compositions that enable the use of alower effective dosage of corticosteroids (referred to as the “steroidsparing effect”) would be highly desirable to avoid unwanted sideeffects. The compounds of the invention provide such a steroid sparingeffect by achieving the desired therapeutic effect while allowing theuse of lower doses and less frequent administration of glucocorticoidsor corticosteroids.

Administration of the compounds of the invention, in pure form or in anappropriate pharmaceutical composition, can be carried out using any ofthe accepted modes of administration of pharmaceutical compositions.Thus, administration can be, for example, orally, buccally (e.g.,sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

As one of skill in the art would expect, the forms of the compounds ofthe invention utilized in a particular pharmaceutical formulation willbe selected (e.g., salts) that possess suitable physical characteristics(e.g., water solubility) that is required for the formulation to beefficacious.

Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

Pharmaceutical compositions suitable for parenteral administrationcomprise sterile aqueous preparations of a compound of the presentinvention. These preparations are preferably administered intravenously,although administration can also be effected by means of subcutaneous,intramuscular, or intradermal injection. Injectable pharmaceuticalformulations are commonly based upon injectable sterile saline,phosphate-buffered saline, oleaginous suspensions, or other injectablecarriers known in the art and are generally rendered sterile andisotonic with the blood. The injectable pharmaceutical formulations maytherefore be provided as a sterile injectable solution or suspension ina nontoxic parenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like. Such injectable pharmaceuticalformulations are formulated according to the known art using suitabledispersing or setting agents and suspending agents. Injectablecompositions will generally contain from 0.1 to 5% w/w of a compound ofthe invention.

Solid dosage forms for oral administration of the compounds includecapsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention is formed by the incorporation of any ofthe normally employed excipients, such as, for example, pharmaceuticalgrades of mannitol, lactose, starch, pregelatinized starch, magnesiumstearate, sodium saccharine, talcum, cellulose ether derivatives,glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Suchsolid pharmaceutical formulations may include formulations, as arewell-known in the art, to provide prolonged or sustained delivery of thedrug to the gastrointestinal tract by any number of mechanisms, whichinclude, but are not limited to, pH sensitive release from the dosageform based on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form to themucosal lining of the intestinal tract, or enzymatic release of theactive drug from the dosage form.

Liquid dosage forms for oral administration of the compounds includeemulsions, microemulsions, solutions, suspensions, syrups, and elixirs,optionally containing pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike. These compositions can also contain additional adjuvants such aswetting, emulsifying, suspending, sweetening, flavoring, and perfumingagents.

Topical dosage forms of the compounds include ointments, pastes, creams,lotions, gels, powders, solutions, sprays, inhalants, eye ointments, eyeor ear drops, impregnated dressings and aerosols, and may containappropriate conventional additives such as preservatives, solvents toassist drug penetration and emollients in ointments and creams. Topicalapplication may be once or more than once per day depending upon theusual medical considerations. Furthermore, preferred compounds for thepresent invention can be administered in intranasal form via topical useof suitable intranasal vehicles. The formulations may also containcompatible conventional carriers, such as cream or ointment bases andethanol or oleyl alcohol for lotions. Such carriers may be present asfrom about 1% up to about 98% of the formulation, more usually they willform up to about 80% of the formulation.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal administration can be presented as discretepatches adapted to remain in intimate contact with the epidermis of therecipient for a prolonged period of time. To be administered in the formof a transdermal delivery system, the dosage administration will, ofcourse, be continuous rather than intermittent throughout the dosageregimen. Such patches suitably contain a compound of the invention in anoptionally buffered, aqueous solution, dissolved and/or dispersed in anadhesive, or dispersed in a polymer. A suitable concentration of theactive compound is about 1% to 35%, preferably about 3% to 15%.

For administration by inhalation, the compounds of the invention areconveniently delivered in the form of an aerosol spray from a pump spraydevice not requiring a propellant gas or from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide, or other suitable gas. In any case, the aerosol spray dosageunit may be determined by providing a valve to deliver a metered amountso that the resulting metered dose inhaler (MDI) is used to administerthe compounds of the invention in a reproducible and controlled way.Such inhaler, nebulizer, or atomizer devices are known in the prior art,for example, in PCT International Publication Nos. WO 97/12687(particularly FIG. 6 thereof, which is the basis for the commercialRESPIMAT® nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, towhich reference is hereby made and each of which is incorporated hereinby reference in their entireties.

Rectal administration can be effected utilizing unit dose suppositoriesin which the compound is admixed with low-melting water-soluble orinsoluble solids such as fats, cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights, or fatty acid esters of polyethylene glycols, or thelike. The active compound is usually a minor component, often from about0.05 to 10% by weight, with the remainder being the base component.

In all of the above pharmaceutical compositions, the compounds of theinvention are formulated with an acceptable carrier or excipient. Thecarriers or excipients used must, of course, be acceptable in the senseof being compatible with the other ingredients of the composition andmust not be deleterious to the patient. The carrier or excipient can bea solid or a liquid, or both, and is preferably formulated with thecompound of the invention as a unit-dose composition, for example, atablet, which can contain from 0.05% to 95% by weight of the activecompound. Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

Generally, a therapeutically effective daily dose is from about 0.001 mgto about 15 mg/kg of body weight per day of a compound of the invention;preferably, from about 0.1 mg to about 10 mg/kg of body weight per day;and most preferably, from about 0.1 mg to about 1.5 mg/kg of body weightper day. For example, for administration to a 70 kg person, the dosagerange would be from about 0.07 mg to about 1050 mg per day of a compoundof the invention, preferably from about 7.0 mg to about 700 mg per day,and most preferably from about 7.0 mg to about 105 mg per day. Somedegree of routine dose optimization may be required to determine anoptimal dosing level and pattern.

Pharmaceutically acceptable carriers and excipients encompass all theforegoing additives and the like.

Examples of Pharmaceutical Formulations

A. TABLETS Component Amount per tablet (mg) active substance 100 lactose140 corn starch 240 polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL500

The finely ground active substance, lactose, and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B. TABLETS Component Amount per tablet (mg) active substance 80 lactose55 corn starch 190 polyvinylpyrrolidone 15 magnesium stearate 2microcrystalline cellulose 35 sodium-carboxymethyl starch 23 TOTAL 400

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose, and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize.

C. COATED TABLETS Component Amount per tablet (mg) active substance 5lactose 30 corn starch 41.5 polyvinylpyrrolidone 3 magnesium stearate0.5 TOTAL 90

The active substance, corn starch, lactose, and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax.

D. CAPSULES Component Amount per capsule (mg) active substance 50 cornstarch 268.5 magnesium stearate 1.5 TOTAL 320

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E. AMPOULE SOLUTION Component Amount per ampoule active substance 50 mgsodium chloride 50 mg water for inj.  5 mL

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg, and50 mg of active substance.

F. SUPPOSITORIES Component Amount per suppository (mg) active substance 50 solid fat 1650 TOTAL 1700

The hard fat is melted. At 40° C., the ground active substance ishomogeneously dispersed therein. The mixture is cooled to 38° C. andpoured into slightly chilled suppository molds.

G. METERING AEROSOL Component Amount active substance 0.005 sorbitantrioleate 0.1 monofluorotrichloromethane and to 100difluorodichloromethane (2:3)

The suspension is transferred into a conventional aerosol container witha metering valve. Preferably, 50 μL of suspension are delivered perspray. The active substance may also be metered in higher doses ifdesired (e.g., 0.02% by weight).

H. POWDER FOR INHALATION Component Amount active substance 1.0 mglactose monohydrate to 25 mg

I. POWDER FOR INHALATION Component Amount active substance 2.0 mglactose monohydrate to 25 mg

J. POWDER FOR INHALATION Component Amount active substance 1.0 mglactose monohydrate to 5 mg

K. POWDER FOR INHALATION Component Amount active substance  2.0 mglactose monohydrate to 5 mg

In Examples H, I, J, and K, the powder for inhalation is produced in theusual way by mixing the individual ingredients together.

1. A compound of Formula (I)

wherein: R¹ and R² are each independently hydrogen or C₁-C₅ alkyl, or R¹and R² together with the carbon atom they are commonly attached to forma C₃-C₆ ring; R³ is a bond or C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl group optionally independently substituted with one to threesubstituent groups, wherein each substituent group of R³ isindependently C₃-C₈ cycloalkyl, aryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy,C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino,C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, C₁-C₅dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano,trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the nitrogenatom is optionally independently mono- or di-substituted by C₁-C₅ alkylor aryl; or ureido wherein either nitrogen atom is optionallyindependently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio whereinthe sulfur atom is optionally oxidized to a sulfoxide or sulfone,wherein each substituent group of R³ is optionally independentlysubstituted with one to three substituent groups selected from methyl,methoxy, halogen, hydroxy, oxo, cyano, or amino; R⁴ is hydrogen, C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy,carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio,nitro, or amino wherein the nitrogen atom is optionally independentlymono- or di-substituted by C₁-C₅ alkyl; or ureido wherein eithernitrogen atom is optionally independently substituted with C₁-C₅ alkyl;or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone; R⁵ and R⁶ are each independently hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl group optionally independentlysubstituted with one to three substituent groups, wherein eachsubstituent group of R⁵ and R⁶ are independently C₃-C₈ cycloalkyl, aryl,heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy,halogen, hydroxy, oxo, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, C₁-C₅ alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone, wherein each substituentgroup of R⁵ and R⁶ is optionally independently substituted with one tothree substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl, or R⁵ and R⁶together with the carbon atom they are commonly attached to form a C₃-C₆ring; X is O, S, or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C₁-C₅ alkyl or aryl and thesulfur atom is optionally oxidized to a sulfoxide or sulfone; Y is anaryl or heteroaryl group, each optionally independently substituted withone to three substituent groups, wherein each substituent group of Y isindependently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈cycloalkyl, aryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy,carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogenatom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxideor sulfone, wherein each substituent group of Y is optionallyindependently substituted with one to three substituent groups selectedfrom methyl, methoxy, halogen, hydroxy, oxo, cyano, or amino; n is 0, 1,2, or 3, or a tautomer, prodrug, solvate, or salt thereof.
 2. Thecompound of Formula (I) according to claim 1, wherein: R¹ and R² areeach independently hydrogen or C₁-C₃ alkyl; R³ is a bond or C₁-C₅ alkylor C₂-C₅ alkenyl group optionally independently substituted with one totwo substituent groups, wherein each substituent group of R³ isindependently C₃-C₆ cycloalkyl, phenyl, methoxy, halogen, hydroxy, oxo,cyano, trifluoromethyl, trifluoromethoxy, or C₁-C₅ alkylthio wherein thesulfur atom is optionally oxidized to a sulfoxide or sulfone, whereineach substituent group of R³ is optionally independently substitutedwith fluorine, chlorine, or bromine; R⁴ is hydrogen, C₁-C₅ alkyl, C₂-C₅alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, furanyl, thienyl,C₁-C₅ alkoxy, halogen, hydroxy, cyano, trifluoromethyl,trifluoromethoxy, or C₁-C₅ alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone; R⁵ and R⁶ are eachindependently hydrogen, C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl; Xis O, NH, or S; Y is a phenyl group independently substituted with oneto two substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy,halogen, hydroxy, cyano, trifluoromethyl, or trifluoromethoxy; n is 1,or a tautomer, prodrug, solvate, or salt thereof.
 3. The compound ofFormula (I) according to claim 2, wherein: R¹ and R² are each methyl; R³is a bond or C₁-C₅ alkyl or C₂-C₅ alkenyl group; R⁴ is hydrogen, C₃-C₆cycloalkyl, phenyl, fluorine, or chlorine; R⁵ and R⁶ are eachindependently hydrogen, methyl, or ethyl; X is O or S; Y is a phenylgroup independently substituted with one to two substituent groupsselected from methoxy, fluorine, chlorine, or hydroxy, or a tautomer,prodrug, solvate, or salt thereof.
 4. The compound of Formula (I)according to claim 1, wherein: R¹ and R² are each methyl; R³is a bond;R⁴ is a C₃-C₅ alkyl or C₃-C₅ alkenyl group; R⁵ is hydrogen or methyl; R⁶is hydrogen; X is O or S; and Y is a 2-methoxyphenyl,2-methoxy-5-fluorophenyl, or 2-chloro-3-hydroxyphenyl group, or atautomer, prodrug, solvate, or salt thereof.
 5. The compound of Formula(I) according to claim 1, wherein: R¹ and R² are each methyl; R³ is aC²-C₄ alkyl group; R⁴ is phenyl group optionally monosubstituted with afluorine or chlorine group; R⁵ is hydrogen or methyl; R⁶ is hydrogen; Xis O or S; and Y is a 2-methoxyphenyl, 2-methoxy-5-fluorophenyl, or2-chloro-3-hydroxyphenyl group, or a tautomer, prodrug, solvate, or saltthereof.
 6. The compound of Formula (I) according to claim 1, wherein:R¹ and R² are each methyl; R³ is a C₁-C₃ alkyl group; R⁴ is a cyclohexylgroup; R⁵ is hydrogen or methyl; R⁶ is hydrogen; X is O or S; and Y is a2-methoxyphenyl, 2-methoxy-5-fluorophenyl, or 2-chloro-3-hydroxyphenylgroup, or a tautomer, prodrug, solvate, or salt thereof.
 7. A compoundselected from:[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]phenylamine;(3,5-Dichlorophenyl)-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine;4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(3,5-Dichlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;Allyl-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]amine;[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]propylamine;4-Allyloxymethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Benzylsulfanylmethyl-2,2-dimethyl-6-phenyl-1,2-dihydroquinoline;4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Benzylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-2,2-dimethyl-6-phenyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(2,6-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;2-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]-N-methylacetamide;6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;3-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]propionicacid methyl ester;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline;4-(4-tert-Butylphenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Cyclohexylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3-methylbutylsulfanylmethyl)-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(3-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(2-ethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;(E)-3-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]acrylicacid ethyl ester;4-(4-Methoxybenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]benzamide;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(prop-2-ene-1-sulfinylmethyl)-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(naphthalen-2-ylsulfanylmethyl)-1,2-dihydroquinoline;[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethylsulfanyl]aceticacid methyl ester;4-(4-Chlorophenylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-2-phenylacetamide;6-(2-Methoxyphenyl)-4-(4-methoxyphenylsulfanylmethyl)-2,2-dimethyl-1,2-dihydroquinoline;N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-N-methylbenzamide;4-Allylsulfanylmethyl-2,2-dimethyl-6-(2-nitrophenyl)-1,2-dihydroquinoline;4-Allylsulfanylmethyl-2,2-dimethyl-6-o-tolyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-dibenzofuran-4-yl-2,2-dimethyl-1,2-dihydroquinoline;N-[6-(2-Methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]-N-methyl-2-phenylacetamide;4-(4-Chlorobenzylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(2-fluorophenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Fluorophenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-biphenyl-2-yl-2,2-dimethyl-1,2-dihydroquinoline;6-Biphenyl-2-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;Thioacetic acidS-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-ylmethyl]ester;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline;4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;2,2-Dimethyl-6-(2-methylsulfanylphenyl)-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(2,5-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2,5-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(3-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(3-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(4-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(4-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(3,4-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(3,4-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline;6-(2,3-Dimethoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(2,3-dimethoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-2,2-dimethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline;2,2-Dimethyl-4-phenethylsulfanylmethyl-6-(2-trifluoromethylphenyl)-1,2-dihydroquinoline;4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline;4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Cyclohexylmethoxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;2-Chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol;3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol;6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-[((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline;4-{1-[2-(2-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(5-isopropyl-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Isopropyl-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-methylbut-2-enyloxy)ethyl]-1,2-dihydroquinoline;4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-{1-[2-(3-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline;4-(1-Allyloxypropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxybutyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxy-3-phenylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxybut-3-enyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxy-2-phenylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxy-2-methylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(Allyloxyphenylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;Allyl-{1-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]ethyl}amine;Allyl-{1-[6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinolin-4-yl]ethyl}methylamine;and4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,or a tautomer, prodrug, solvate, or salt thereof.
 8. A compound selectedfrom:4-Allylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(Furan-3-ylmethylsulfanylmethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-propylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(2-methylbutylsulfanylmethyl)-1,2-dihydroquinoline;4-Cyclohexylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(3-methylbutylsulfanylmethyl)-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline;4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-Benzo[1,3]dioxol-5-yl-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(3-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-phenylpropoxy)ethyl]-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-((E)-3-phenylallyloxy)ethyl]-1,2-dihydroquinoline;4-[1-(2-Cyclohexylethoxy)ethyl]-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Cyclohexylmethoxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;2-Chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol;3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol;6-(2-Methoxyphenyl)-2,2-dimethyl-4-{1-[((E)-pent-2-enyl)oxy]ethyl}-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(3-methylbut-2-enyloxy)ethyl]-1,2-dihydroquinoline;4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-{1-[2-(3-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline;4-(1-Allyloxypropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxy-2-methylpropyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;and4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,or a tautomer, prodrug, solvate, or salt thereof.
 9. A compound selectedfrom:6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-(1-phenethylsulfanylethyl)-1,2-dihydroquinoline;4-(1-Allylsulfanylethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-(1-Allyloxyethyl)-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-Allylsulfanylmethyl-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinoline;4-{1-[((E)-But-2-enyl)oxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;2-Chloro-3-(2,2-dimethyl-4-phenethylsulfanylmethyl-1,2-dihydroquinolin-6-yl)phenol;3-(4-Allylsulfanylmethyl-2,2-dimethyl-1,2-dihydroquinolin-6-yl)-2-chlorophenol;4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;6-(5-Fluoro-2-methoxyphenyl)-2,2-dimethyl-4-(1-phenethyloxyethyl)-1,2-dihydroquinoline;4-{1-[2-(4-Chlorophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(2-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;4-{1-[2-(3-Bromophenyl)ethoxy]ethyl}-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline;6-(2-Methoxyphenyl)-2,2-dimethyl-4-[1-(1-methylallyloxy)ethyl]-1,2-dihydroquinoline;and4-(1-Allyloxyethyl)-6-(5-fluoro-2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline,or a tautomer, prodrug, solvate, or salt thereof.
 10. A pharmaceuticalcomposition comprising an effective amount of a compound according toone of claims 1 to 9, or a tautomer, prodrug, solvate, or salt thereof,and a pharmaceutically acceptable excipient or carrier.
 11. A method oftreating a disease-state or condition selected from: type II diabetesand obesity, in a patient in need of such treatment, the methodcomprising administering to the patient an effective amount of apharmaceutically acceptable compound according to one of claims 1 to 9,or a tautomer, prodrug, solvate, or salt thereof.
 12. A method of makinga compound of Formula (I)

where R³, R⁴, R⁵, R⁶, X, Y, and n are as defined in claim 1 and R¹ andR² are each methyl, the method comprising: reacting the compound ofFormula (VII) with a nucleophile R³R⁴XH_(m), where XH_(m) is NH₂, SH, orOH, in the presence of a suitable base to form the compound of Formula(I)


13. A method of making a compound of Formula (I)

where R³, R⁴, R⁵, R⁶, X, Y, and n are as defined in claim 1 and R¹ andR² are each methyl, the method comprising: (a) reacting a4-halonitrobenzene or 4-nitroaryltriflate of Formula (II) with anarylboronic acid of Formula (III) in the presence of a suitablepalladium catalyst and base to form a biaryl compound of Formula (IV)

(b) reducing the nitro group of the biaryl compound of Formula (I) byreaction with a suitable reducing agent to form a compound of Formula(V)

(c) reacting the compound of Formula (V) with acetone in the presence ofiodine to form a compound of Formula (VI)

(d) reacting the compound of Formula (VI) with a suitable brominatingagent to form a compound of Formula (VII)

(e) reacting the compound of Formula (VII) with a nucleophileR³R⁴XH_(m), where XH_(m) is NH₂, SH, or OH, in the presence of asuitable base to form the compound of Formula (I)